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Pathak T, Benson JC, Tang PW, Trebak M, Hempel N. Crosstalk between calcium and reactive oxygen species signaling in cancer revisited. Cell Calcium 2025; 127:103014. [PMID: 40139005 DOI: 10.1016/j.ceca.2025.103014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
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Affiliation(s)
- Trayambak Pathak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - J Cory Benson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Priscilla W Tang
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Nadine Hempel
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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Silva ÁJC, de Lavor MSL. Nitroxidative Stress, Cell-Signaling Pathways, and Manganese Porphyrins: Therapeutic Potential in Neuropathic Pain. Int J Mol Sci 2025; 26:2050. [PMID: 40076672 PMCID: PMC11900433 DOI: 10.3390/ijms26052050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/23/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Neuropathic pain, a debilitating condition arising from somatosensory system damage, significantly impacts quality of life, leading to anxiety, self-mutilation, and depression. Oxidative and nitrosative stress, an imbalance between reactive oxygen and nitrogen species (ROS/RNS) and antioxidant defenses, plays a crucial role in its pathophysiology. While reactive species are essential for physiological functions, excessive levels can cause cellular component damage, leading to neuronal dysfunction and pain. This review highlights the complex interactions between reactive species, antioxidant systems, cell signaling, and neuropathic pain. We discuss the physiological roles of ROS/RNS and the detrimental effects of oxidative and nitrosative stress. Furthermore, we explore the potential of manganese porphyrins, compounds with antioxidant properties, as promising therapeutic agents to mitigate oxidative stress and alleviate neuropathic pain by targeting key cellular pathways involved in pain. Further research is needed to fully understand their therapeutic potential in managing neuropathic pain in human and non-human animals.
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Affiliation(s)
| | - Mário Sérgio Lima de Lavor
- Department of Agricultural and Environmental Sciences, State University of Santa Cruz (UESC), Ilhéus 45662-900, BA, Brazil;
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Schleinhege R, Neumann I, Oeckinghaus A, Schwab A, Pethő Z. A CNA-35-based high-throughput fibrosis assay reveals ORAI1 as a regulator of collagen release from pancreatic stellate cells. Matrix Biol 2025; 135:70-86. [PMID: 39662708 DOI: 10.1016/j.matbio.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/22/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
RATIONALE Pancreatic stellate cells (PSCs) produce a collagen-rich connective tissue in chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Ca2+-permeable ion channels such as ORAI1 are known to affect PSC proliferation and myofibroblastic phenotype. However, it is unknown whether these channels play a role in collagen secretion. METHODS Using the PSC cell line PS-1, we characterized their cell-derived matrices using staining, mass spectroscopy, and cell migration assays. We developed and validated a high-throughput in vitro fibrosis assay to rapidly determine collagen quantity either with Sirius Red or, in the optimized version, with the collagen-binding peptide CNA-35-tdTomato. We assessed collagen deposition upon stimulating cells with transforming growth factor β1 (TGF-β1) and/or vitamin C without or with ORAI1 modulation. Orai1 expression was assessed by immunohistochemistry in the fibrotic tumor tissue of a murine PDAC model (KPfC). RESULTS We found that TGF-β1 and vitamin C promote collagen deposition from PSCs. We used small interfering RNA (siRNA) and the inhibitor Synta-66 to demonstrate that ORAI1 regulates collagen secretion of PSCs but not NIH-3T3 fibroblasts. Physiological levels of vitamin C induce a drastic increase of the intracellular [Ca2+] in PSCs, with Synta-66 inhibiting Ca2+ influx. Lastly, we revealed Orai1 expression in cancer-associated fibroblasts (CAFs) in murine PDAC (KPfC) samples. CONCLUSION In conclusion, our study introduces a robust in vitro assay for fibrosis and identifies ORAI1 as being engaged in PSC-driven fibrosis.
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Affiliation(s)
- Rieke Schleinhege
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany
| | - Ilka Neumann
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany
| | - Andrea Oeckinghaus
- Institute of Molecular Tumor Biology, University of Münster, 48149, Germany
| | - Albrecht Schwab
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany
| | - Zoltán Pethő
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany.
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Ahuja K, Raju S, Dahiya S, Motiani RK. ROS and calcium signaling are critical determinant of skin pigmentation. Cell Calcium 2025; 125:102987. [PMID: 39708588 PMCID: PMC7617625 DOI: 10.1016/j.ceca.2024.102987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
Pigmentation is a protective phenomenon that shields skin cells from UV-induced DNA damage. Perturbations in pigmentation pathways predispose to skin cancers and lead to pigmentary disorders. These ailments impart psychological trauma and severely affect the patients' quality of life. Emerging literature suggests that reactive oxygen species (ROS) and calcium (Ca2+) signaling modules regulate physiological pigmentation. Further, pigmentary disorders are associated with dysregulated ROS homeostasis and changes in Ca2+ dynamics. Here, we systemically review the literature that demonstrates key role of ROS and Ca2+ signaling in pigmentation and pigmentary disorders. Further, we discuss recent studies, which have revealed that organelle-specific Ca2+ transport mechanisms are critical determinant of pigmentation. Importantly, we deliberate upon the possibility of clinical management of pigmentary disorders by therapeutically targeting ROS generation and cellular Ca2+ handling toolkit. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention. Although an important role of ROS and Ca2+ signaling in regulating skin pigmentation has emerged, the underlying molecular mechanisms remain poorly understood. In future, it would be vital to investigate in detail the signaling cascades that connect perturbed ROS homeostasis and Ca2+ signaling to human pigmentary disorders.
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Affiliation(s)
- Kriti Ahuja
- Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Sharon Raju
- Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Sakshi Dahiya
- Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Rajender K Motiani
- Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India.
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Feijóo V, Tajada S, Méndez-Mena A, Núñez L, Villalobos C. Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca 2+ entry in tumor cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119862. [PMID: 39437852 DOI: 10.1016/j.bbamcr.2024.119862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/09/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024]
Abstract
Most cancer cells show the Warburg effect, the rewiring of aerobic metabolism to glycolysis due to defective mitochondrial ATP synthesis. As a consequence, tumor cells display enhanced mitochondrial potential (∆Ψ), the driving force for mitochondrial Ca2+ uptake. Mitochondria control the Ca2+-dependent inactivation of store-operated channels (SOCs), leading to enhanced and sustained store-operated Ca2+ entry (SOCE) involved in cancer hallmarks. We asked here whether the transfer of mitochondria (mitoception) from normal cells to tumor cells may reverse SOCE remodeling in cancer cells. For this end, we labeled mitochondria in normal NCM460 human colonic cells, isolated them and transferred them to tumor HT29 cells. We tested the viability and efficiency of mitoception using flow cytometry and confocal microscopy, as well as calcium imaging to investigate the effects of mitoception on SOCE. Our results show that mitoception of tumor HT29 cells with normal mitochondria restores a low ∆Ψ and SOCE. Conversely, self-mitoception of tumor HT29 cells with tumor cell mitochondria increases further ∆Ψ and SOCE, thus excluding the possibility that effects of mitoception are due to increased mitochondrial mass. Strikingly, mitoception of normal NCM460 cells with tumor cell mitochondria has no effects on either ∆Ψ or SOCE. These results are consistent with the previous proposal that transformed mitochondria may modulate SOC channels involved in SOCE. Further research is warranted to test whether mitoception of cancer cells with normal mitochondria may reverse Ca2+ remodeling associated to cancer.
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Affiliation(s)
- Verónica Feijóo
- Excellence Unit Institute of Biomedicine and Molecular Genetics of Valladolid (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain
| | - Sendoa Tajada
- Excellence Unit Institute of Biomedicine and Molecular Genetics of Valladolid (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain; Department of Biochemistry and Molecular Biology and Physiology, School of Medicine, University of Valladolid, 47005 Valladolid, Spain
| | - Alejandra Méndez-Mena
- Excellence Unit Institute of Biomedicine and Molecular Genetics of Valladolid (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain
| | - Lucía Núñez
- Excellence Unit Institute of Biomedicine and Molecular Genetics of Valladolid (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain; Department of Biochemistry and Molecular Biology and Physiology, School of Medicine, University of Valladolid, 47005 Valladolid, Spain
| | - Carlos Villalobos
- Excellence Unit Institute of Biomedicine and Molecular Genetics of Valladolid (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain.
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Shumanska M, Lodygin D, Gibhardt CS, Ickes C, Stejerean-Todoran I, Krause LCM, Pahl K, Jacobs LJHC, Paluschkiwitz A, Liu S, Boshnakovska A, Voigt N, Legler TJ, Haubrock M, Mitkovski M, Poschmann G, Rehling P, Dennerlein S, Riemer J, Flügel A, Bogeski I. Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses. EMBO Rep 2025; 26:407-442. [PMID: 39623165 PMCID: PMC11772621 DOI: 10.1038/s44319-024-00313-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 01/29/2025] Open
Abstract
T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector T-cells display elevated mCa2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUaKD), diminishes mCa2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUaKD in rat CD4+ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that mCa2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.
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Affiliation(s)
- Magdalena Shumanska
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Dmitri Lodygin
- Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Christine S Gibhardt
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Christian Ickes
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Ioana Stejerean-Todoran
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Lena C M Krause
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Kira Pahl
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Lianne J H C Jacobs
- Redox Metabolism, Institute of Biochemistry and CECAD, University of Cologne, Cologne, Germany
| | - Andrea Paluschkiwitz
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Shuya Liu
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Angela Boshnakovska
- Department of Cellular Biochemistry, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Niels Voigt
- Institute of Pharmacology and Toxicology, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Tobias J Legler
- Department of Transfusion Medicine, University Medical Centre, Göttingen, Germany
| | - Martin Haubrock
- Department of Medical Bioinformatics, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Miso Mitkovski
- City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Gereon Poschmann
- Institute for Molecular Medicine, Proteome Research, University Hospital and Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Peter Rehling
- Department of Cellular Biochemistry, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Sven Dennerlein
- Department of Cellular Biochemistry, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Jan Riemer
- Redox Metabolism, Institute of Biochemistry and CECAD, University of Cologne, Cologne, Germany
| | - Alexander Flügel
- Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre, Georg-August-University, Göttingen, Germany
| | - Ivan Bogeski
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany.
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7
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Stejerean-Todoran I, Gibhardt CS, Bogeski I. Calcium signals as regulators of ferroptosis in cancer. Cell Calcium 2024; 124:102966. [PMID: 39504596 DOI: 10.1016/j.ceca.2024.102966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024]
Abstract
The field of ferroptosis research has grown exponentially since this form of cell death was first identified over a decade ago. Ferroptosis, an iron- and ROS-dependent type of cell death, is controlled by various metabolic pathways, including but not limited to redox and calcium (Ca2+) homeostasis, iron fluxes, mitochondrial function and lipid metabolism. Importantly, therapy-resistant tumors are particularly susceptible to ferroptotic cell death, rendering ferroptosis a promising therapeutic strategy against numerous malignancies. Calcium signals are important regulators of both cancer progression and cell death, with recent studies indicating their involvement in ferroptosis. Cells undergoing ferroptosis are characterized by plasma membrane rupture and the formation of nanopores, which facilitate influx of ions such as Ca2+ into the affected cells. Furthermore, mitochondrial Ca²⁺ levels have been implicated in directly influencing the cellular response to ferroptosis. Despite the remarkable progress made in the field, our understanding of the contribution of Ca2+ signals to ferroptosis remains limited. Here, we summarize key connections between Ca²⁺ signaling and ferroptosis in cancer pathobiology and discuss their potential therapeutic significance.
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Affiliation(s)
- Ioana Stejerean-Todoran
- Molecular Physiology, Department of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
| | - Christine S Gibhardt
- Molecular Physiology, Department of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
| | - Ivan Bogeski
- Molecular Physiology, Department of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany.
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Makio T, Chen J, Simmen T. ER stress as a sentinel mechanism for ER Ca 2+ homeostasis. Cell Calcium 2024; 124:102961. [PMID: 39471738 DOI: 10.1016/j.ceca.2024.102961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 11/01/2024]
Abstract
Endoplasmic reticulum (ER) stress is triggered upon the interference with oxidative protein folding that aims to produce fully folded, disulfide-bonded and glycosylated proteins, which are then competent to exit the ER. Many of the enzymes catalyzing this process require the binding of Ca2+ ions, including the chaperones BiP/GRP78, calnexin and calreticulin. The induction of ER stress with a variety of drugs interferes with chaperone Ca2+ binding, increases cytosolic Ca2+through the opening of ER Ca2+ channels, and activates store-operated Ca2+ entry (SOCE). Posttranslational modifications (PTMs) of the ER Ca2+ handling proteins through ER stress-dependent phosphorylation or oxidation control these mechanisms, as demonstrated in the case of the sarco/endoplasmic reticulum ATPase (SERCA), inositol 1,4,5 trisphosphate receptors (IP3Rs) or stromal interaction molecule 1 (STIM1). Their aim is to restore ER Ca2+ homeostasis but also to increase Ca2+ transfer from the ER to mitochondria during ER stress. This latter function boosts ER bioenergetics, but also triggers apoptosis if ER Ca2+ signaling persists. ER Ca2+ toolkit oxidative modifications upon ER stress can occur within the ER lumen or in the adjacent cytosol. Enzymes involved in this redox control include ER oxidoreductin 1 (ERO1) or the thioredoxin-family protein disulfide isomerases (PDI) and ERp57. A tight, but adaptive connection between ER Ca2+ content, ER stress and mitochondrial readouts allows for the proper functioning of many tissues, including skeletal muscle, the liver, and the pancreas, where ER stress either maintains or compromises their function, depending on its extent and context. Upon mutation of key regulators of ER Ca2+ signaling, diseases such as muscular defects (e.g., from mutated selenoprotein N, SEPN1/SELENON), or diabetes (e.g., from mutated PERK) are the result.
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Affiliation(s)
- Tadashi Makio
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada
| | - Junsheng Chen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada.
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Saint-Martin Willer A, Montani D, Capuano V, Antigny F. Orai1/STIMs modulators in pulmonary vascular diseases. Cell Calcium 2024; 121:102892. [PMID: 38735127 DOI: 10.1016/j.ceca.2024.102892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/27/2024] [Accepted: 04/23/2024] [Indexed: 05/14/2024]
Abstract
Calcium (Ca2+) is a secondary messenger that regulates various cellular processes. However, Ca2+ mishandling could lead to pathological conditions. Orai1 is a Ca2+channel contributing to the store-operated calcium entry (SOCE) and plays a critical role in Ca2+ homeostasis in several cell types. Dysregulation of Orai1 contributed to severe combined immune deficiency syndrome, some cancers, pulmonary arterial hypertension (PAH), and other cardiorespiratory diseases. During its activation process, Orai1 is mainly regulated by stromal interacting molecule (STIM) proteins, especially STIM1; however, many other regulatory partners have also been recently described. Increasing knowledge about these regulatory partners provides a better view of the downstream signalling pathways of SOCE and offers an excellent opportunity to decipher Orai1 dysregulation in these diseases. These proteins participate in other cellular functions, making them attractive therapeutic targets. This review mainly focuses on Orai1 regulatory partners in the physiological and pathological conditions of the pulmonary circulation and inflammation.
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Affiliation(s)
- Anaïs Saint-Martin Willer
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 Hypertension pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - David Montani
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 Hypertension pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Véronique Capuano
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 Hypertension pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Hôptal Marie Lannelongue, Groupe Hospitalier Paris Saint-Joseph, Le Plessis-Robinson, France
| | - Fabrice Antigny
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 Hypertension pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
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10
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Abdelnaby AE, Trebak M. Store-Operated Ca 2+ Entry in Fibrosis and Tissue Remodeling. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2024; 7:25152564241291374. [PMID: 39659877 PMCID: PMC11629433 DOI: 10.1177/25152564241291374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 08/29/2024] [Accepted: 09/27/2024] [Indexed: 12/12/2024]
Abstract
Fibrosis is a pathological condition characterized by excessive tissue deposition of extracellular matrix (ECM) components, leading to scarring and impaired function across multiple organ systems. This complex process is mediated by a dynamic interplay between cell types, including myofibroblasts, fibroblasts, immune cells, epithelial cells, and endothelial cells, each contributing distinctively through various signaling pathways. Critical to the regulatory mechanisms involved in fibrosis is store-operated calcium entry (SOCE), a calcium entry pathway into the cytosol active at the endoplasmic reticulum-plasma membrane contact sites and common to all cells. This review addresses the multifactorial nature of fibrosis with a focus on the pivotal roles of different cell types. We highlight the essential functions of myofibroblasts in ECM production, the transformation of fibroblasts, and the participation of immune cells in modulating the fibrotic landscape. We emphasize the contributions of SOCE in these different cell types to fibrosis, by exploring the involvement of SOCE in cellular functions such as proliferation, migration, secretion, and inflammatory responses. The examination of the cellular and molecular mechanisms of fibrosis and the role of SOCE in these mechanisms offers the potential of targeting SOCE as a therapeutic strategy for mitigating or reversing fibrosis.
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Affiliation(s)
- Ahmed Emam Abdelnaby
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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11
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Gross S, Womer L, Kappes DJ, Soboloff J. Multifaceted control of T cell differentiation by STIM1. Trends Biochem Sci 2023; 48:1083-1097. [PMID: 37696713 PMCID: PMC10787584 DOI: 10.1016/j.tibs.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 08/08/2023] [Accepted: 08/18/2023] [Indexed: 09/13/2023]
Abstract
In T cells, stromal interaction molecule (STIM) and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. This review focuses on novel STIM-dependent mechanisms for control of Ca2+ signals during T cell activation and its impact on mitochondrial function and transcriptional activation for control of T cell differentiation and function. We highlight areas that require further work including the roles of plasma membrane Ca2+ ATPase (PMCA) and partner of STIM1 (POST) in controlling Orai function. A major knowledge gap also exists regarding the independence of T cell development from STIM and Orai, despite compelling evidence that it requires Ca2+ signals. Resolving these and other outstanding questions ensures that the field will remain active for many years to come.
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Affiliation(s)
- Scott Gross
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Lauren Womer
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | | | - Jonathan Soboloff
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
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12
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Brun C, Chalet L, Moulin F, Bochaton T, Ducreux S, Paillard M, Crola Da Silva C. A bibliometric analysis: Ca 2+ fluxes and inflammatory phenotyping by flow cytometry in peripheral blood mononuclear cells. Front Immunol 2023; 14:1272809. [PMID: 37901222 PMCID: PMC10611513 DOI: 10.3389/fimmu.2023.1272809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/02/2023] [Indexed: 10/31/2023] Open
Abstract
Background The immune system, composed of organs, tissues, cells, and proteins, is the key to protecting the body from external biological attacks and inflammation. The latter occurs in several pathologies, such as cancers, type 1 diabetes, and human immunodeficiency virus infection. Immunophenotyping by flow cytometry is the method of choice for diagnosing these pathologies. Under inflammatory conditions, the peripheral blood mononuclear cells (PBMCs) are partially activated and generate intracellular pathways involving Ca2+-dependent signaling cascades leading to transcription factor expression. Ca2+ signaling is typically studied by microscopy in cell lines but can present some limitations to explore human PBMCs, where flow cytometry can be a good alternative. Objective In this review, we dived into the research field of inflammation and Ca2+ signaling in PBMCs. We aimed to investigate the structure and evolution of this field in a physio-pathological context, and then we focused our review on flow cytometry analysis of Ca2+ fluxes in PBMCs. Methods From 1984 to 2022, 3865 articles on inflammation and Ca2+ signaling in PBMCs were published, according to The Clarivate Web of Science (WOS) database used in this review. A bibliometric study was designed for this collection and consisted of a co-citation and bibliographic coupling analysis. Results The co-citation analysis was performed on 133 articles: 4 clusters highlighted the global context of Ca2+ homeostasis, including chemical probe development, identification of the leading players in Ca2+ signaling, and the link with chemokine production in immune cell function. Next, the bibliographic coupling analysis combined 998 articles in 8 clusters. This analysis outlined the mechanisms of PBMC activation, from signal integration to cellular response. Further explorations of the bibliographic coupling network, focusing on flow cytometry, revealed 21 articles measuring cytosolic Ca2+ in PBMCs, with only 5 since 2016. This final query showed that Ca2+ signaling analysis in human PBMCs using flow cytometry is still underdeveloped and investigates mainly the cytosolic Ca2+ compartment. Conclusion Our review uncovers remaining knowledge gaps of intracellular players involved in Ca2+ signaling in PBMCs, such as reticulum and mitochondria, and presents flow cytometry as a solid option to supplement gold-standard microscopy studies.
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Affiliation(s)
- Camille Brun
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
| | - Lucie Chalet
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
- Olea Medical, La Ciotat, France
| | - Florentin Moulin
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
| | - Thomas Bochaton
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
- Hospices Civils de Lyon, Hôpital Louis Pradel, Services D’explorations Fonctionnelles Cardiovasculaires et CIC de Lyon, Lyon, France
| | - Sylvie Ducreux
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
| | - Melanie Paillard
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
| | - Claire Crola Da Silva
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Bron, France
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13
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Plasterer C, Semenikhina M, Tsaih SW, Flister MJ, Palygin O. NNAT is a novel mediator of oxidative stress that suppresses ER + breast cancer. Mol Med 2023; 29:87. [PMID: 37400769 PMCID: PMC10318825 DOI: 10.1186/s10020-023-00673-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/30/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Neuronatin (NNAT) was recently identified as a novel mediator of estrogen receptor-positive (ER+) breast cancer cell proliferation and migration, which correlated with decreased tumorigenic potential and prolonged patient survival. However, despite these observations, the molecular and pathophysiological role(s) of NNAT in ER + breast cancer remains unclear. Based on high protein homology with phospholamban, we hypothesized that NNAT mediates the homeostasis of intracellular calcium [Ca2+]i levels and endoplasmic reticulum (EndoR) function, which is frequently disrupted in ER + breast cancer and other malignancies. METHODS To evaluate the role of NNAT on [Ca2+]i homeostasis, we used a combination of bioinformatics, gene expression and promoter activity assays, CRISPR gene manipulation, pharmacological tools and confocal imaging to characterize the association between ROS, NNAT and calcium signaling. RESULTS Our data indicate that NNAT localizes predominantly to EndoR and lysosome, and genetic manipulation of NNAT levels demonstrated that NNAT modulates [Ca2+]i influx and maintains Ca2+ homeostasis. Pharmacological inhibition of calcium channels revealed that NNAT regulates [Ca2+]i levels in breast cancer cells through the interaction with ORAI but not the TRPC signaling cascade. Furthermore, NNAT is transcriptionally regulated by NRF1, PPARα, and PPARγ and is strongly upregulated by oxidative stress via the ROS and PPAR signaling cascades. CONCLUSION Collectively, these data suggest that NNAT expression is mediated by oxidative stress and acts as a regulator of Ca2+ homeostasis to impact ER + breast cancer proliferation, thus providing a molecular link between the longstanding observation that is accumulating ROS and altered Ca2+ signaling are key oncogenic drivers of cancer.
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Affiliation(s)
- Cody Plasterer
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Marharyta Semenikhina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Shirng-Wern Tsaih
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA
| | - Michael J Flister
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.
| | - Oleg Palygin
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
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14
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Slowik EJ, Stankoska K, Bui NN, Pasieka B, Conrad D, Zapp J, Hoth M, Bogeski I, Kappl R. The calcium channel modulator 2-APB hydrolyzes in physiological buffers and acts as an effective radical scavenger and inhibitor of the NADPH oxidase 2. Redox Biol 2023; 61:102654. [PMID: 36889081 PMCID: PMC10009725 DOI: 10.1016/j.redox.2023.102654] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/06/2023] Open
Abstract
2-aminoethoxydiphenyl borate (2-APB) is commonly used as a tool to modulate calcium signaling in physiological studies. 2-APB has a complex pharmacology and acts as activator or inhibitor of a variety of Ca2+ channels and transporters. While unspecific, 2-APB is one of the most-used agents to modulate store-operated calcium entry (SOCE) mediated by the STIM-gated Orai channels. Due to its boron core structure, 2-APB tends to readily hydrolyze in aqueous environment, a property that results in a complex physicochemical behavior. Here, we quantified the degree of hydrolysis in physiological conditions and identified the hydrolysis products diphenylborinic acid and 2-aminoethanol by NMR. Notably, we detected a high sensitivity of 2-APB/diphenylborinic acid towards decomposition by hydrogen peroxide to compounds such as phenylboronic acid, phenol, and boric acid, which were, in contrast to 2-APB itself and diphenylborinic acid, insufficient to affect SOCE in physiological experiments. Consequently, the efficacy of 2-APB as a Ca2+ signal modulator strongly depends on the reactive oxygen species (ROS) production within the experimental system. The antioxidant behavior of 2-APB towards ROS and its resulting decomposition are inversely correlated to its potency to modulate Ca2+ signaling as shown by electron spin resonance spectroscopy (ESR) and Ca2+ imaging. Finally, we observed a strong inhibitory effect of 2-APB, i.e., its hydrolysis product diphenylborinic acid, on NADPH oxidase (NOX2) activity in human monocytes. These new 2-APB properties are highly relevant for Ca2+ and redox signaling studies and for pharmacological application of 2-APB and related boron compounds.
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Affiliation(s)
- Ewa Jasmin Slowik
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany
| | - Katerina Stankoska
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany
| | - Nhat Nguyen Bui
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany
| | - Bastian Pasieka
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany
| | - David Conrad
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany; Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Saarland University Faculty of Medicine, 66421, Homburg, Germany
| | - Josef Zapp
- Department of Pharmaceutical Biology, Saarland University, 66123, Saarbrücken, Germany
| | - Markus Hoth
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany
| | - Ivan Bogeski
- Molecular Physiology, Department of Cardiovascular Physiology, UMG, 37073, Göttingen, Germany
| | - Reinhard Kappl
- Department of Biophysics, Faculty of Medicine, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421, Homburg, Germany.
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15
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Dong XY. Calcium Ion Channels in Saccharomyces cerevisiae. J Fungi (Basel) 2023; 9:jof9050524. [PMID: 37233235 DOI: 10.3390/jof9050524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
Regulating calcium ion (Ca2+) channels to improve the cell cycle and metabolism is a promising technology, ensuring increased cell growth, differentiation, and/or productivity. In this regard, the composition and structure of Ca2+ channels play a vital role in controlling the gating states. In this review, Saccharomyces cerevisiae, as a model eukaryotic organism and an essential industrial microorganism, was used to discuss the effect of its type, composition, structure, and gating mechanism on the activity of Ca2+ channels. Furthermore, the advances in the application of Ca2+ channels in pharmacology, tissue engineering, and biochemical engineering are summarized, with a special focus on exploring the receptor site of Ca2+ channels for new drug design strategies and different therapeutic uses, targeting Ca2+ channels to produce functional replacement tissues, creating favorable conditions for tissue regeneration, and regulating Ca2+ channels to enhance biotransformation efficiency.
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Affiliation(s)
- Xiao-Yu Dong
- College of Life and Health, Dalian University, Dalian 116622, China
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16
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Bouron A. Neuronal Store-Operated Calcium Channels. Mol Neurobiol 2023:10.1007/s12035-023-03352-5. [PMID: 37118324 DOI: 10.1007/s12035-023-03352-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/13/2023] [Indexed: 04/30/2023]
Abstract
The endoplasmic reticulum (ER) is the major intracellular calcium (Ca2+) storage compartment in eukaryotic cells. In most instances, the mobilization of Ca2+ from this store is followed by a delayed and sustained uptake of Ca2+ through Ca2+-permeable channels of the cell surface named store-operated Ca2+ channels (SOCCs). This gives rise to a store-operated Ca2+ entry (SOCE) that has been thoroughly investigated in electrically non-excitable cells where it is the principal regulated Ca2+ entry pathway. The existence of this Ca2+ route in neurons has long been a matter of debate. However, a growing body of experimental evidence indicates that the recruitment of Ca2+ from neuronal ER Ca2+ stores generates a SOCE. The present review summarizes the main studies supporting the presence of a depletion-dependent Ca2+ entry in neurons. It also addresses the question of the molecular composition of neuronal SOCCs, their expression, pharmacological properties, as well as their physiological relevance.
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Affiliation(s)
- Alexandre Bouron
- Université Grenoble Alpes, CNRS, CEA, Inserm UA13 BGE, 38000, Grenoble, France.
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17
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Emrich SM, Yoast RE, Zhang X, Fike AJ, Wang YH, Bricker KN, Tao AY, Xin P, Walter V, Johnson MT, Pathak T, Straub AC, Feske S, Rahman ZSM, Trebak M. Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells. eLife 2023; 12:e84708. [PMID: 36803766 PMCID: PMC9998091 DOI: 10.7554/elife.84708] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/16/2023] [Indexed: 02/23/2023] Open
Abstract
The essential role of store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels in T cells is well established. In contrast, the contribution of individual Orai isoforms to SOCE and their downstream signaling functions in B cells are poorly understood. Here, we demonstrate changes in the expression of Orai isoforms in response to B cell activation. We show that both Orai3 and Orai1 mediate native CRAC channels in B cells. The combined loss of Orai1 and Orai3, but not Orai3 alone, impairs SOCE, proliferation and survival, nuclear factor of activated T cells (NFAT) activation, mitochondrial respiration, glycolysis, and the metabolic reprogramming of primary B cells in response to antigenic stimulation. Nevertheless, the combined deletion of Orai1 and Orai3 in B cells did not compromise humoral immunity to influenza A virus infection in mice, suggesting that other in vivo co-stimulatory signals can overcome the requirement of BCR-mediated CRAC channel function in B cells. Our results shed important new light on the physiological roles of Orai1 and Orai3 proteins in SOCE and the effector functions of B lymphocytes.
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Affiliation(s)
- Scott M Emrich
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Ryan E Yoast
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Xuexin Zhang
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Adam J Fike
- Department of Microbiology and Immunology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Yin-Hu Wang
- Department of Pathology, New York University School of MedicineNew YorkUnited States
| | - Kristen N Bricker
- Department of Microbiology and Immunology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Anthony Y Tao
- Department of Pathology, New York University School of MedicineNew YorkUnited States
| | - Ping Xin
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
- Vascular Medicine Institute, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Vonn Walter
- Department of Public Health Sciences, Pennsylvania State University College of MedicineHersheyUnited States
| | - Martin T Johnson
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Trayambak Pathak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
- Vascular Medicine Institute, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Adam C Straub
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
- Vascular Medicine Institute, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Stefan Feske
- Department of Pathology, New York University School of MedicineNew YorkUnited States
| | - Ziaur SM Rahman
- Department of Microbiology and Immunology, Pennsylvania State University College of MedicineHersheyUnited States
| | - Mohamed Trebak
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of MedicineHersheyUnited States
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
- Vascular Medicine Institute, University of Pittsburgh School of MedicinePittsburghUnited States
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18
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Correa BH, Moreira CR, Hildebrand ME, Vieira LB. The Role of Voltage-Gated Calcium Channels in Basal Ganglia Neurodegenerative Disorders. Curr Neuropharmacol 2023; 21:183-201. [PMID: 35339179 PMCID: PMC10190140 DOI: 10.2174/1570159x20666220327211156] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/11/2022] [Accepted: 03/14/2022] [Indexed: 11/22/2022] Open
Abstract
Calcium (Ca2+) plays a central role in regulating many cellular processes and influences cell survival. Several mechanisms can disrupt Ca2+ homeostasis to trigger cell death, including oxidative stress, mitochondrial damage, excitotoxicity, neuroinflammation, autophagy, and apoptosis. Voltage-gated Ca2+ channels (VGCCs) act as the main source of Ca2+ entry into electrically excitable cells, such as neurons, and they are also expressed in glial cells such as astrocytes and oligodendrocytes. The dysregulation of VGCC activity has been reported in both Parkinson's disease (PD) and Huntington's (HD). PD and HD are progressive neurodegenerative disorders (NDs) of the basal ganglia characterized by motor impairment as well as cognitive and psychiatric dysfunctions. This review will examine the putative role of neuronal VGCCs in the pathogenesis and treatment of central movement disorders, focusing on PD and HD. The link between basal ganglia disorders and VGCC physiology will provide a framework for understanding the neurodegenerative processes that occur in PD and HD, as well as a possible path towards identifying new therapeutic targets for the treatment of these debilitating disorders.
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Affiliation(s)
- Bernardo H.M. Correa
- Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Carlos Roberto Moreira
- Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Luciene Bruno Vieira
- Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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19
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Jardin I, Berna-Erro A, Nieto-Felipe J, Macias A, Sanchez-Collado J, Lopez JJ, Salido GM, Rosado JA. Similarities and Differences between the Orai1 Variants: Orai1α and Orai1β. Int J Mol Sci 2022; 23:ijms232314568. [PMID: 36498894 PMCID: PMC9735889 DOI: 10.3390/ijms232314568] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/16/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Orai1, the first identified member of the Orai protein family, is ubiquitously expressed in the animal kingdom. Orai1 was initially characterized as the channel responsible for the store-operated calcium entry (SOCE), a major mechanism that allows cytosolic calcium concentration increments upon receptor-mediated IP3 generation, which results in intracellular Ca2+ store depletion. Furthermore, current evidence supports that abnormal Orai1 expression or function underlies several disorders. Orai1 is, together with STIM1, the key element of SOCE, conducting the Ca2+ release-activated Ca2+ (CRAC) current and, in association with TRPC1, the store-operated Ca2+ (SOC) current. Additionally, Orai1 is involved in non-capacitative pathways, as the arachidonate-regulated or LTC4-regulated Ca2+ channel (ARC/LRC), store-independent Ca2+ influx activated by the secretory pathway Ca2+-ATPase (SPCA2) and the small conductance Ca2+-activated K+ channel 3 (SK3). Furthermore, Orai1 possesses two variants, Orai1α and Orai1β, the latter lacking 63 amino acids in the N-terminus as compared to the full-length Orai1α form, which confers distinct features to each variant. Here, we review the current knowledge about the differences between Orai1α and Orai1β, the implications of the Ca2+ signals triggered by each variant, and their downstream modulatory effect within the cell.
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20
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Immunosenescence in Aging-Related Vascular Dysfunction. Int J Mol Sci 2022; 23:ijms232113269. [PMID: 36362055 PMCID: PMC9654630 DOI: 10.3390/ijms232113269] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
The immunosenescence-related disproportion in T lymphocytes may have important consequences for endothelial dysfunction, which is a key event in vascular aging. The study was designed to assess the prognostic values of the inflammatory-immune profile to better predict and prevent vascular diseases associated with old age. Eighty individuals aged 70.9 ± 5.3 years were allocated to a low- (LGI) or high-grade inflammation (HGI) group based on CRP (<3 or ≥3 mg/L) as a conventional risk marker of cardiovascular diseases. Significant changes in inflammatory and endothelium-specific variables IL-1β, IL-6, TNFα, oxLDL, H2O2, NO, 3-nitrotyrosine, and endothelial progenitor cells (OR 7.61, 95% CI 2.56−29.05, p < 0.0001), confirmed their interplay in vascular inflammation. The flow-cytometry analysis demonstrated a high disproportion in T lymphocytes CD4+ and CD8+ between LGI and HGI groups. CRP was <3 mg/mL for the CD4/CD8 ratio within the reference values ≥ 1 or ≤2.5, unlike for the CD4/CD8 ratio < 1 and >2.5. The odds ratios for the distribution of CD4+ (OR 5.98, 95% CI 0.001−0.008, p < 0.001), CD8+ (OR 0.23, 95% CI 0.08−0.59, p < 0.01), and CD8CD45RO+ T naïve cells (OR 0.27, 95% CI 0.097−0.695, p < 0.01) and CD4/CD8 (OR 5.69, 95% CI 2.07−17.32, p < 0.001) indicated a potential diagnostic value of T lymphocytes for clinical prognosis in aging-related vascular dysfunction.
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21
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Kuo CL, Ponneri Babuharisankar A, Lin YC, Lien HW, Lo YK, Chou HY, Tangeda V, Cheng LC, Cheng AN, Lee AYL. Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend? J Biomed Sci 2022; 29:74. [PMID: 36154922 PMCID: PMC9511749 DOI: 10.1186/s12929-022-00859-2] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 09/19/2022] [Indexed: 12/07/2022] Open
Abstract
The major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.
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Affiliation(s)
- Cheng-Liang Kuo
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan
| | - Ananth Ponneri Babuharisankar
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan.,Joint PhD Program in Molecular Medicine, NHRI & NCU, Zhunan, Miaoli, 35053, Taiwan
| | - Ying-Chen Lin
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan
| | - Hui-Wen Lien
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan
| | - Yu Kang Lo
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan
| | - Han-Yu Chou
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan
| | - Vidhya Tangeda
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan.,Joint PhD Program in Molecular Medicine, NHRI & NCU, Zhunan, Miaoli, 35053, Taiwan
| | - Li-Chun Cheng
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - An Ning Cheng
- Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan
| | - Alan Yueh-Luen Lee
- National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053, Taiwan. .,Joint PhD Program in Molecular Medicine, NHRI & NCU, Zhunan, Miaoli, 35053, Taiwan. .,Department of Life Sciences, College of Health Sciences and Technology, National Central University, Zhongli, Taoyuan, 32001, Taiwan. .,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan. .,Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
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22
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Wang L, Cao Z, Wang Z, Guo J, Wen J. Reactive oxygen species associated immunoregulation post influenza virus infection. Front Immunol 2022; 13:927593. [PMID: 35967412 PMCID: PMC9373727 DOI: 10.3389/fimmu.2022.927593] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
An appropriate level of reactive oxygen species (ROS) is necessary for cell proliferation, signaling transduction, and apoptosis due to their highly reactive character. ROS are generated through multiple metabolic pathways under a fine-tuned control between oxidant and antioxidant signaling. A growing number of evidence has proved their highly relevant role in modulating inflammation during influenza virus infection. As a network of biological process for protecting organism from invasion of pathogens, immune system can react and fight back through either innate immune system or adaptive immune system, or both. Herein, we provide a review about the mechanisms of ROS generation when encounter influenza virus infection, and how the imbalanced level of ROS influences the replication of virus. We also summarize the pathways used by both the innate and adaptive immune system to sense and attack the invaded virus and abnormal levels of ROS. We further review the limitation of current strategies and discuss the direction of future work.
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Affiliation(s)
- Lan Wang
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, United States,UCLA Acquired Immune Deficiency Syndrome (AIDS) Institute, University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Zheng Cao
- Department of Chemical and Biomolecular Engineering, University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Zi Wang
- Department of Chemical and Biomolecular Engineering, University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Jimin Guo
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, United States,UCLA Acquired Immune Deficiency Syndrome (AIDS) Institute, University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Jing Wen
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, United States,UCLA Acquired Immune Deficiency Syndrome (AIDS) Institute, University of California Los Angeles (UCLA), Los Angeles, CA, United States,*Correspondence: Jing Wen,
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23
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Wang L, Noyer L, Wang YH, Tao AY, Li W, Zhu J, Saavedra P, Hoda ST, Yang J, Feske S. ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages. J Gen Physiol 2022; 154:213360. [PMID: 35861698 PMCID: PMC9532584 DOI: 10.1085/jgp.202213104] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/24/2022] [Indexed: 01/23/2023] Open
Abstract
Ca2+ signals regulate the function of many immune cells and promote immune responses to infection, cancer, and autoantigens. Ca2+ influx in immune cells is mediated by store-operated Ca2+ entry (SOCE) that results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels. The CRAC channel is formed by three plasma membrane proteins, ORAI1, ORAI2, and ORAI3. Of these, ORAI1 is the best studied and plays important roles in immune function. By contrast, the physiological role of ORAI3 in immune cells remains elusive. We show here that ORAI3 is expressed in many immune cells including macrophages, B cells, and T cells. To investigate ORAI3 function in immune cells, we generated Orai3-/- mice. The development of lymphoid and myeloid cells in the thymus and bone marrow was normal in Orai3-/- mice, as was the composition of immune cells in secondary lymphoid organs. Deletion of Orai3 did not affect SOCE in B cells and T cells but moderately enhanced SOCE in macrophages. Orai3-deficient macrophages, B cells, and T cells had normal effector functions in vitro. Immune responses in vivo, including humoral immunity (T cell dependent or independent) and antitumor immunity, were normal in Orai3-/- mice. Moreover, Orai3-/- mice showed no differences in susceptibility to septic shock, experimental autoimmune encephalomyelitis, or collagen-induced arthritis. We conclude that despite its expression in myeloid and lymphoid cells, ORAI3 appears to be dispensable or redundant for physiological and pathological immune responses mediated by these cells.
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Affiliation(s)
- Liwei Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Lucile Noyer
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Yin-Hu Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Anthony Y. Tao
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Wenyi Li
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Jingjie Zhu
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Pedro Saavedra
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Syed T. Hoda
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Jun Yang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Stefan Feske
- Department of Pathology, New York University Grossman School of Medicine, New York, NY,Correspondence to Stefan Feske:
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24
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Audero MM, Prevarskaya N, Fiorio Pla A. Ca 2+ Signalling and Hypoxia/Acidic Tumour Microenvironment Interplay in Tumour Progression. Int J Mol Sci 2022; 23:7377. [PMID: 35806388 PMCID: PMC9266881 DOI: 10.3390/ijms23137377] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 01/18/2023] Open
Abstract
Solid tumours are characterised by an altered microenvironment (TME) from the physicochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hypoxia results from uncontrolled proliferation, aberrant vascularization and altered cancer cell metabolism. Tumour cellular apparatus adapts to hypoxia by altering its metabolism and behaviour, increasing its migratory and metastatic abilities by the acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance via the selection of more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are pH and hypoxia sensors and alterations in Ca2+ homeostasis in cancer progression and vascularization have been extensively reported. In the present review, we present an up-to-date and critical view on Ca2+ permeable ion channels, with a major focus on TRPs, SOCs and PIEZO channels, which are modulated by tumour hypoxia and acidosis, as well as the consequent role of the altered Ca2+ signals on cancer progression hallmarks. We believe that a deeper comprehension of the Ca2+ signalling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutic targets.
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Affiliation(s)
- Madelaine Magalì Audero
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Natalia Prevarskaya
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
| | - Alessandra Fiorio Pla
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
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25
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Wang L, Jing L, Zhang Q, Li S, Wang Y, Zhao H. Lead induced thymic immunosuppression in Japanese quail (Coturnix japonica) via oxidative stress-based T cell receptor pathway signaling inhibition. J Inorg Biochem 2022; 235:111950. [DOI: 10.1016/j.jinorgbio.2022.111950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 11/28/2022]
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26
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Xue C, Dong N, Shan A. Putative role of STING-mitochondria associated membrane crosstalk in immunity. Trends Immunol 2022; 43:513-522. [DOI: 10.1016/j.it.2022.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 04/29/2022] [Accepted: 04/29/2022] [Indexed: 01/03/2023]
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27
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Collins HE, Zhang D, Chatham JC. STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases. FRONTIERS IN AGING 2022; 3:876785. [PMID: 35821821 PMCID: PMC9261457 DOI: 10.3389/fragi.2022.876785] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/30/2022] [Indexed: 01/19/2023]
Abstract
Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.
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Affiliation(s)
- Helen E. Collins
- Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Dingguo Zhang
- Division of Molecular and Cellular Pathology, Department of PathologyUniversity of Alabama at Birmingham, Birmingham, AL, United States
| | - John C. Chatham
- Division of Molecular and Cellular Pathology, Department of PathologyUniversity of Alabama at Birmingham, Birmingham, AL, United States,*Correspondence: John C. Chatham,
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28
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Title: p53 alters intracellular Ca2+ signaling through regulation of TRPM4. Cell Calcium 2022; 104:102591. [DOI: 10.1016/j.ceca.2022.102591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/08/2022] [Accepted: 04/18/2022] [Indexed: 12/11/2022]
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29
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Inflammation and Nitro-oxidative Stress as Drivers of Endocannabinoid System Aberrations in Mood Disorders and Schizophrenia. Mol Neurobiol 2022; 59:3485-3503. [PMID: 35347586 DOI: 10.1007/s12035-022-02800-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 03/13/2022] [Indexed: 01/02/2023]
Abstract
The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB1 and CB2) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB1 expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB2 upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB1 and CB2 have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A2 activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia.
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30
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Abstract
Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ signaling pathway that is evolutionarily conserved across eukaryotes. SOCE is triggered physiologically when the endoplasmic reticulum (ER) Ca2+ stores are emptied through activation of inositol 1,4,5-trisphosphate receptors. SOCE is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels, which are highly Ca2+ selective. Upon store depletion, the ER Ca2+-sensing STIM proteins aggregate and gain extended conformations spanning the ER-plasma membrane junctional space to bind and activate Orai, the pore-forming proteins of hexameric CRAC channels. In recent years, studies on STIM and Orai tissue-specific knockout mice and gain- and loss-of-function mutations in humans have shed light on the physiological functions of SOCE in various tissues. Here, we describe recent findings on the composition of native CRAC channels and their physiological functions in immune, muscle, secretory, and neuronal systems to draw lessons from transgenic mice and human diseases caused by altered CRAC channel activity.
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Affiliation(s)
- Scott M Emrich
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA;
| | - Ryan E Yoast
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA;
| | - Mohamed Trebak
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA;
- Department of Pharmacology and Chemical Biology and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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31
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Humer C, Romanin C, Höglinger C. Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions. Cells 2022; 11:371. [PMID: 35159181 PMCID: PMC8834118 DOI: 10.3390/cells11030371] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/14/2022] [Accepted: 01/15/2022] [Indexed: 11/16/2022] Open
Abstract
Orai1, the Ca2+-selective pore in the plasma membrane, is one of the key components of the Ca2+release-activated Ca2+ (CRAC) channel complex. Activated by the Ca2+ sensor in the endoplasmic reticulum (ER) membrane, stromal interaction molecule 1 (STIM1), via direct interaction when ER luminal Ca2+ levels recede, Orai1 helps to maintain Ca2+ homeostasis within a cell. It has already been proven that the C-terminus of Orai1 is indispensable for channel activation. However, there is strong evidence that for CRAC channels to function properly and maintain all typical hallmarks, such as selectivity and reversal potential, additional parts of Orai1 are needed. In this review, we focus on these sites apart from the C-terminus; namely, the second loop and N-terminus of Orai1 and on their multifaceted role in the functioning of CRAC channels.
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Affiliation(s)
| | | | - Carmen Höglinger
- Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria; (C.H.); (C.R.)
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32
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Mokrane N, Snabi Y, Cens T, Guiramand J, Charnet P, Bertaud A, Menard C, Rousset M, de Jesus Ferreira MC, Thibaud JB, Cohen-Solal C, Vignes M, Roussel J. Manipulations of Glutathione Metabolism Modulate IP 3-Mediated Store-Operated Ca 2+ Entry on Astroglioma Cell Line. Front Aging Neurosci 2022; 13:785727. [PMID: 34975458 PMCID: PMC8719003 DOI: 10.3389/fnagi.2021.785727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/01/2021] [Indexed: 02/03/2023] Open
Abstract
The regulation of the redox status involves the activation of intracellular pathways as Nrf2 which provides hormetic adaptations against oxidative stress in response to environmental stimuli. In the brain, Nrf2 activation upregulates the formation of glutathione (GSH) which is the primary antioxidant system mainly produced by astrocytes. Astrocytes have also been shown to be themselves the target of oxidative stress. However, how changes in the redox status itself could impact the intracellular Ca2+ homeostasis in astrocytes is not known, although this could be of great help to understand the neuronal damage caused by oxidative stress. Indeed, intracellular Ca2+ changes in astrocytes are crucial for their regulatory actions on neuronal networks. We have manipulated GSH concentration in astroglioma cells with selective inhibitors and activators of the enzymes involved in the GSH cycle and analyzed how this could modify Ca2+ homeostasis. IP3-mediated store-operated calcium entry (SOCE), obtained after store depletion elicited by Gq-linked purinergic P2Y receptors activation, are either sensitized or desensitized, following GSH depletion or increase, respectively. The desensitization may involve decreased expression of the proteins STIM2, Orai1, and Orai3 which support SOCE mechanism. The sensitization process revealed by exposing cells to oxidative stress likely involves the increase in the activity of Calcium Release-Activated Channels (CRAC) and/or in their membrane expression. In addition, we observe that GSH depletion drastically impacts P2Y receptor-mediated changes in membrane currents, as evidenced by large increases in Ca2+-dependent K+ currents. We conclude that changes in the redox status of astrocytes could dramatically modify Ca2+ responses to Gq-linked GPCR activation in both directions, by impacting store-dependent Ca2+-channels, and thus modify cellular excitability under purinergic stimulation.
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Affiliation(s)
- Nawfel Mokrane
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | - Yassin Snabi
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | - Thierry Cens
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France
| | - Janique Guiramand
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France
| | - Pierre Charnet
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France
| | - Anaïs Bertaud
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | - Claudine Menard
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | - Matthieu Rousset
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France
| | - Marie-Céleste de Jesus Ferreira
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | | | - Catherine Cohen-Solal
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | - Michel Vignes
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
| | - Julien Roussel
- UMR 5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, France.,Department of Biological Sciences, Université de Montpellier, Montpellier, France
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33
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Johnson J, Blackman R, Gross S, Soboloff J. Control of STIM and Orai function by post-translational modifications. Cell Calcium 2022; 103:102544. [PMID: 35151050 PMCID: PMC8960353 DOI: 10.1016/j.ceca.2022.102544] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/17/2022] [Accepted: 01/26/2022] [Indexed: 12/15/2022]
Abstract
Store-operated calcium entry (SOCE) is mediated by the endoplasmic reticulum (ER) Ca2+ sensors stromal interaction molecules (STIM1 and STIM2) and the plasma membrane Orai (Orai1, Orai2, Orai3) Ca2+ channels. Although primarily regulated by ER Ca2+ content, there have been numerous studies over the last 15 years demonstrating that all 5 proteins are also regulated through post-translational modification (PTM). Focusing primarily on phosphorylation, glycosylation and redox modification, this review focuses on how PTMs modulate the key events in SOCE; Ca2+ sensing, STIM translocation, Orai interaction and/or Orai1 activation.
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34
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Fresquez AM, White C. Extracellular cysteines C226 and C232 mediate hydrogen sulfide-dependent inhibition of Orai3-mediated store-operated calcium entry. Am J Physiol Cell Physiol 2022; 322:C38-C48. [PMID: 34788146 PMCID: PMC8759961 DOI: 10.1152/ajpcell.00490.2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The gaseous signaling molecule hydrogen sulfide (H2S) physiologically regulates store-operated Ca2+ entry (SOCE). The SOCE machinery consists of the plasma membrane-localized Orai channels (Orai1-3) and endoplasmic reticulum-localized stromal interaction molecule (STIM)1 and STIM2 proteins. H2S inhibits Orai3- but not Orai1- or Orai2-mediated SOCE. The current objective was to define the mechanism by which H2S selectively modifies Orai3. We measured SOCE and STIM1/Orai3 dynamics and interactions in HEK293 cells exogenously expressing fluorescently tagged human STIM1 and Orai3 in the presence and absence of the H2S donor GYY4137. Two cysteines (C226 and C232) are present in Orai3 that are absent in the Orai1 and Orai2. When we mutated either of these cysteines to serine, alone or in combination, SOCE inhibition by H2S was abolished. We also established that inhibition was dependent on an interaction with STIM1. To further define the effects of H2S on STIM1/Orai3 interaction, we performed a series of fluorescence recovery after photobleaching (FRAP), colocalization, and fluorescence resonance energy transfer (FRET) experiments. Treatment with H2S did not affect the mobility of Orai3 in the membrane, nor did it influence STIM1/Orai3 puncta formation or STIM1-Orai3 protein-protein interactions. These data support a model in which H2S modification of Orai3 at cysteines 226 and 232 limits SOCE evoked upon store depletion and STIM1 engagement, by a mechanism independent of the interaction between Orai3 and STIM1.
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Affiliation(s)
- Adriana M. Fresquez
- 1Discipline of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois,2Center for Cancer Cell Biology, Immunology, and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois
| | - Carl White
- 1Discipline of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois,2Center for Cancer Cell Biology, Immunology, and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois
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35
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Carreras-Sureda A, Abrami L, Ji-Hee K, Wang WA, Henry C, Frieden M, Didier M, van der Goot FG, Demaurex N. S-acylation by ZDHHC20 targets ORAI1 channels to lipid rafts for efficient Ca 2+ signaling by Jurkat T cell receptors at the immune synapse. eLife 2021; 10:72051. [PMID: 34913437 PMCID: PMC8683079 DOI: 10.7554/elife.72051] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 11/29/2021] [Indexed: 12/29/2022] Open
Abstract
Efficient immune responses require Ca2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 promotes TCR recruitment and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel remained in cholesterol-poor domains upon enforced ZDHHC20 expression and was recruited less efficiently to the IS along with actin and TCR. Our results establish S-acylation as a critical regulator of ORAI1 channel trafficking and function at the IS and reveal that ORAI1 S-acylation enhances TCR recruitment to the synapse.
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Affiliation(s)
| | - Laurence Abrami
- Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Kim Ji-Hee
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Wen-An Wang
- Department of Cell Physiology and Metabolism, Geneva, Switzerland
| | | | - Maud Frieden
- Department of Cell Physiology and Metabolism, Geneva, Switzerland
| | - Monica Didier
- Department of Cell Physiology and Metabolism, Geneva, Switzerland
| | - F Gisou van der Goot
- Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Nicolas Demaurex
- Department of Cell Physiology and Metabolism, Geneva, Switzerland
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36
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Bassoy EY, Walch M, Martinvalet D. Reactive Oxygen Species: Do They Play a Role in Adaptive Immunity? Front Immunol 2021; 12:755856. [PMID: 34899706 PMCID: PMC8653250 DOI: 10.3389/fimmu.2021.755856] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022] Open
Abstract
The immune system protects the host from a plethora of microorganisms and toxins through its unique ability to distinguish self from non-self. To perform this delicate but essential task, the immune system relies on two lines of defense. The innate immune system, which is by nature fast acting, represents the first line of defense. It involves anatomical barriers, physiological factors as well as a subset of haematopoietically-derived cells generically call leukocytes. Activation of the innate immune response leads to a state of inflammation that serves to both warn about and combat the ongoing infection and delivers the antigenic information of the invading pathogens to initiate the slower but highly potent and specific second line of defense, the adaptive immune system. The adaptive immune response calls on T lymphocytes as well as the B lymphocytes essential for the elimination of pathogens and the establishment of the immunological memory. Reactive oxygen species (ROS) have been implicated in many aspects of the immune responses to pathogens, mostly in innate immune functions, such as the respiratory burst and inflammasome activation. Here in this mini review, we focus on the role of ROS in adaptive immunity. We examine how ROS contribute to T-cell biology and discuss whether this activity can be extrapolated to B cells.
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Affiliation(s)
- Esen Yonca Bassoy
- International Society of Liver Surgeons (ISLS), Cankaya Ankara, Turkey.,Departments of Immunology and Cancer Biology, College of Medicine and Science, Mayo Clinic, Scottsdale, AZ, United States
| | - Michael Walch
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Denis Martinvalet
- Department of Biomedical Sciences, University of Padua, Padova, Italy.,Veneto Institute of Molecular Medicine, Padova, Italy
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37
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Rychkov GY, Zhou FH, Adams MK, Brierley SM, Ma L, Barritt GJ. Orai1- and Orai2-, but not Orai3-mediated I CRAC is regulated by intracellular pH. J Physiol 2021; 600:623-643. [PMID: 34877682 DOI: 10.1113/jp282502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Three Orai (Orai1, Orai2, and Orai3) and two stromal interaction molecule (STIM1 and STIM2) mammalian protein homologues constitute major components of the store-operated Ca2+ entry mechanism. When co-expressed with STIM1, Orai1, Orai2 and Orai3 form highly selective Ca2+ channels with properties of Ca2+ release-activated Ca2+ (CRAC) channels. Despite the high level of homology between Orai proteins, CRAC channels formed by different Orai isoforms have distinctive properties, particularly with regards to Ca2+ -dependent inactivation, inhibition/potentiation by 2-aminoethyl diphenylborinate and sensitivity to reactive oxygen species. This study characterises and compares the regulation of Orai1, Orai2- and Orai3-mediated CRAC current (ICRAC ) by intracellular pH (pHi ). Using whole-cell patch clamping of HEK293T cells heterologously expressing Orai and STIM1, we show that ICRAC formed by each Orai homologue has a unique sensitivity to changes in pHi . Orai1-mediated ICRAC exhibits a strong dependence on pHi of both current amplitude and the kinetics of Ca2+ -dependent inactivation. In contrast, Orai2 amplitude, but not kinetics, depends on pHi , whereas Orai3 shows no dependence on pHi at all. Investigation of different Orai1-Orai3 chimeras suggests that pHi dependence of Orai1 resides in both the N-terminus and intracellular loop 2, and may also involve pH-dependent interactions with STIM1. KEY POINTS: It has been shown previously that Orai1/stromal interaction molecule 1 (STIM1)-mediated Ca2+ release-activated Ca2+ current (ICRAC ) is inhibited by intracellular acidification and potentiated by intracellular alkalinisation. The present study reveals that CRAC channels formed by each of the Orai homologues Orai1, Orai2 and Orai3 has a unique sensitivity to changes in intracellular pH (pHi ). The amplitude of Orai2 current is affected by the changes in pHi similarly to the amplitude of Orai1. However, unlike Orai1, fast Ca2+ -dependent inactivation of Orai2 is unaffected by acidic pHi . In contrast to both Orai1 and Orai2, Orai3 is not sensitive to pHi changes. Domain swapping between Orai1 and Orai3 identified the N-terminus and intracellular loop 2 as the molecular structures responsible for Orai1 regulation by pHi . Reduction of ICRAC dependence on pHi seen in a STIM1-independent Orai1 mutant suggested that some parts of STIM1 are also involved in ICRAC modulation by pHi .
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Affiliation(s)
- Grigori Y Rychkov
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Fiona H Zhou
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Melissa K Adams
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Stuart M Brierley
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.,Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, South Australia, Australia
| | - Linlin Ma
- College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia, Australia.,Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia
| | - Greg J Barritt
- College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia, Australia
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Sanchez-Collado J, Jardin I, López JJ, Ronco V, Salido GM, Dubois C, Prevarskaya N, Rosado JA. Role of Orai3 in the Pathophysiology of Cancer. Int J Mol Sci 2021; 22:ijms222111426. [PMID: 34768857 PMCID: PMC8584145 DOI: 10.3390/ijms222111426] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 01/12/2023] Open
Abstract
The mammalian exclusive Orai3 channel participates in the generation and/or modulation of two independent Ca2+ currents, the store-operated current, Icrac, involving functional interactions between the stromal interaction molecules (STIM), STIM1/STIM2, and Orai1/Orai2/Orai3, as well as the store-independent arachidonic acid (AA) (or leukotriene C4)-regulated current Iarc, which involves Orai1, Orai3 and STIM1. Overexpression of functional Orai3 has been described in different neoplastic cells and cancer tissue samples as compared to non-tumor cells or normal adjacent tissue. In these cells, Orai3 exhibits a cell-specific relevance in Ca2+ influx. In estrogen receptor-positive breast cancer cells and non-small cell lung cancer (NSCLC) cells store-operated Ca2+ entry (SOCE) is strongly dependent on Orai3 expression while in colorectal cancer and pancreatic adenocarcinoma cells Orai3 predominantly modulates SOCE. On the other hand, in prostate cancer cells Orai3 expression has been associated with the formation of Orai1/Orai3 heteromeric channels regulated by AA and reduction in SOCE, thus leading to enhanced proliferation. Orai3 overexpression is associated with supporting several cancer hallmarks, including cell cycle progression, proliferation, migration, and apoptosis resistance. This review summarizes the current knowledge concerning the functional role of Orai3 in the pathogenesis of cancer.
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Affiliation(s)
- Jose Sanchez-Collado
- Cell Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, 10003 Caceres, Spain; (J.S.-C.); (I.J.); (V.R.); (G.M.S.)
| | - Isaac Jardin
- Cell Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, 10003 Caceres, Spain; (J.S.-C.); (I.J.); (V.R.); (G.M.S.)
| | - Jose J. López
- Cell Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, 10003 Caceres, Spain; (J.S.-C.); (I.J.); (V.R.); (G.M.S.)
- Correspondence: (J.J.L.); (J.A.R.)
| | - Victor Ronco
- Cell Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, 10003 Caceres, Spain; (J.S.-C.); (I.J.); (V.R.); (G.M.S.)
| | - Gines M. Salido
- Cell Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, 10003 Caceres, Spain; (J.S.-C.); (I.J.); (V.R.); (G.M.S.)
| | - Charlotte Dubois
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologiesa, University of Lille, 59650 Villeneuve d’Ascq, France; (C.D.); (N.P.)
| | - Natalia Prevarskaya
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologiesa, University of Lille, 59650 Villeneuve d’Ascq, France; (C.D.); (N.P.)
| | - Juan A. Rosado
- Cell Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, 10003 Caceres, Spain; (J.S.-C.); (I.J.); (V.R.); (G.M.S.)
- Correspondence: (J.J.L.); (J.A.R.)
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Nan J, Li J, Lin Y, Saif Ur Rahman M, Li Z, Zhu L. The interplay between mitochondria and store-operated Ca 2+ entry: Emerging insights into cardiac diseases. J Cell Mol Med 2021; 25:9496-9512. [PMID: 34564947 PMCID: PMC8505841 DOI: 10.1111/jcmm.16941] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/14/2022] Open
Abstract
Store‐operated Ca2+ entry (SOCE) machinery, including Orai channels, TRPCs, and STIM1, is key to cellular calcium homeostasis. The following characteristics of mitochondria are involved in the physiological and pathological regulation of cells: mitochondria mediate calcium uptake through calcium uniporters; mitochondria are regulated by mitochondrial dynamic related proteins (OPA1, MFN1/2, and DRP1) and form mitochondrial networks through continuous fission and fusion; mitochondria supply NADH to the electron transport chain through the Krebs cycle to produce ATP; under stress, mitochondria will produce excessive reactive oxygen species to regulate mitochondria‐endoplasmic reticulum interactions and the related signalling pathways. Both SOCE and mitochondria play critical roles in mediating cardiac hypertrophy, diabetic cardiomyopathy, and cardiac ischaemia‐reperfusion injury. All the mitochondrial characteristics mentioned above are determinants of SOCE activity, and vice versa. Ca2+ signalling dictates the reciprocal regulation between mitochondria and SOCE under the specific pathological conditions of cardiomyocytes. The coupling of mitochondria and SOCE is essential for various pathophysiological processes in the heart. Herein, we review the research focussing on the reciprocal regulation between mitochondria and SOCE and provide potential interplay patterns in cardiac diseases.
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Affiliation(s)
- Jinliang Nan
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, China
| | - Jiamin Li
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, China
| | - Yinuo Lin
- Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Zhejiang Province, Wenzhou, China
| | - Muhammad Saif Ur Rahman
- Zhejiang University-University of Edinburgh Biomedical Institute, Haining, Zhejiang, China.,Clinical Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengzheng Li
- Department of Neurology, Research Institute of Experimental Neurobiology, The First Affiliated Hospital, Wenzhou Medical University, Zhejiang Province, Wenzhou, China
| | - Lingjun Zhu
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, China
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40
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Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases. Cells 2021; 10:cells10102518. [PMID: 34685498 PMCID: PMC8533710 DOI: 10.3390/cells10102518] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/14/2021] [Accepted: 09/21/2021] [Indexed: 01/08/2023] Open
Abstract
Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca2+. Then, STIM1 translocates into discrete ER-plasma membrane (PM) junctions where it directly interacts with and activates plasma membrane Orai1 channels to refill ER with Ca2+. Furthermore, Ca2+ entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store-operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca2+. Furthermore, it is now clear that STIM1 may inhibit Ca2+ currents mediated by L-type Ca2+ channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca2+ homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection.
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41
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Negri S, Faris P, Moccia F. Reactive Oxygen Species and Endothelial Ca 2+ Signaling: Brothers in Arms or Partners in Crime? Int J Mol Sci 2021; 22:ijms22189821. [PMID: 34575985 PMCID: PMC8465413 DOI: 10.3390/ijms22189821] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/20/2022] Open
Abstract
An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.
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42
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Yoast RE, Emrich SM, Zhang X, Xin P, Arige V, Pathak T, Benson JC, Johnson MT, Abdelnaby AE, Lakomski N, Hempel N, Han JM, Dupont G, Yule DI, Sneyd J, Trebak M. The Mitochondrial Ca 2+ uniporter is a central regulator of interorganellar Ca 2+ transfer and NFAT activation. J Biol Chem 2021; 297:101174. [PMID: 34499925 PMCID: PMC8496184 DOI: 10.1016/j.jbc.2021.101174] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial Ca2+ uptake tailors the strength of stimulation of plasma membrane phospholipase C–coupled receptors to that of cellular bioenergetics. However, how Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) shapes receptor-evoked interorganellar Ca2+ signaling is unknown. Here, we used CRISPR/Cas9 gene knockout, subcellular Ca2+ imaging, and mathematical modeling to show that MCU is a universal regulator of intracellular Ca2+ signaling across mammalian cell types. MCU activity sustains cytosolic Ca2+ signaling by preventing Ca2+-dependent inactivation of store-operated Ca2+ release–activated Ca2+ channels and by inhibiting Ca2+ extrusion. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca2+ responses to store depletion. Physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca2+ oscillations, endoplasmic reticulum Ca2+ refilling, nuclear translocation of nuclear factor for activated T cells transcription factors, and cell proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Our data show that MCU has dual counterbalancing functions at the cytosol–mitochondria interface, whereby the cell-specific MCU-dependent cytosolic Ca2+ clearance and buffering capacity of mitochondria reciprocally regulate interorganellar Ca2+ transfer and nuclear factor for activated T cells nuclear translocation during receptor-evoked signaling. These findings highlight the critical dual function of the MCU not only in the acute Ca2+ buffering by mitochondria but also in shaping endoplasmic reticulum and cytosolic Ca2+ signals that regulate cellular transcription and function.
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Affiliation(s)
- Ryan E Yoast
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Scott M Emrich
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Xuexin Zhang
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Ping Xin
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Vikas Arige
- Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, USA
| | - Trayambak Pathak
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - J Cory Benson
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Martin T Johnson
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Ahmed Emam Abdelnaby
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Natalia Lakomski
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Nadine Hempel
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Jung Min Han
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Geneviève Dupont
- Unité de Chronobiologie Théorique, Université Libre de Bruxelles, Brussels, Belgium
| | - David I Yule
- Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, USA
| | - James Sneyd
- Department of Mathematics, The University of Auckland, Auckland, New Zealand
| | - Mohamed Trebak
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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Tiffner A, Derler I. Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology. Int J Mol Sci 2021; 22:8020. [PMID: 34360783 PMCID: PMC8347056 DOI: 10.3390/ijms22158020] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 11/21/2022] Open
Abstract
Ca2+ ion channels are critical in a variety of physiological events, including cell growth, differentiation, gene transcription and apoptosis. One such essential entry pathway for calcium into the cell is the Ca2+ release-activated Ca2+ (CRAC) channel. It consists of the Ca2+ sensing protein, stromal interaction molecule 1 (STIM1) located in the endoplasmic reticulum (ER) and a Ca2+ ion channel Orai in the plasma membrane. The Orai channel family includes three homologues Orai1, Orai2 and Orai3. While Orai1 is the "classical" Ca2+ ion channel within the CRAC channel complex and plays a universal role in the human body, there is increasing evidence that Orai2 and Orai3 are important in specific physiological and pathophysiological processes. This makes them an attractive target in drug discovery, but requires a detailed understanding of the three Orai channels and, in particular, their differences. Orai channel activation is initiated via Ca2+ store depletion, which is sensed by STIM1 proteins, and induces their conformational change and oligomerization. Upon STIM1 coupling, Orai channels activate to allow Ca2+ permeation into the cell. While this activation mechanism is comparable among the isoforms, they differ by a number of functional and structural properties due to non-conserved regions in their sequences. In this review, we summarize the knowledge as well as open questions in our current understanding of the three isoforms in terms of their structure/function relationship, downstream signaling and physiology as well as pathophysiology.
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Affiliation(s)
| | - Isabella Derler
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria;
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44
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Wu L, Lian W, Zhao L. Calcium signaling in cancer progression and therapy. FEBS J 2021; 288:6187-6205. [PMID: 34288422 DOI: 10.1111/febs.16133] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/19/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023]
Abstract
The old Greek aphorism 'Panta Rhei' ('everything flows') is true for all living things in general. As a dynamic process, calcium signaling plays fundamental roles in cellular activities under both normal and pathological conditions, with recent researches uncovering its involvement in cell proliferation, migration, survival, gene expression, and more. The major question we address here is how calcium signaling affects cancer progression and whether it could be targeted to combine with classic chemotherapeutics or emerging immunotherapies to improve their efficacy.
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Affiliation(s)
- Ling Wu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Weidong Lian
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
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45
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Slaats J, Dieteren CE, Wagena E, Wolf L, Raaijmakers TK, van der Laak JA, Figdor CG, Weigelin B, Friedl P. Metabolic Screening of Cytotoxic T-cell Effector Function Reveals the Role of CRAC Channels in Regulating Lethal Hit Delivery. Cancer Immunol Res 2021; 9:926-938. [PMID: 34226201 DOI: 10.1158/2326-6066.cir-20-0741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 02/24/2021] [Accepted: 04/30/2021] [Indexed: 11/16/2022]
Abstract
Cytotoxic T lymphocytes (CTL) mediate cytotoxicity toward tumor cells by multistep cell-cell interactions. However, the tumor microenvironment can metabolically perturb local CTL effector function. CTL activity is typically studied in two-dimensional (2D) liquid coculture, which is limited in recapitulating the mechanisms and efficacy of the multistep CTL effector response. We here developed a microscopy-based, automated three-dimensional (3D) interface coculture model suitable for medium-throughput screening to delineate the steps and CTL effector mechanisms affected by microenvironmental perturbation. CTL effector function was compromised by deregulated redox homeostasis, deficient mitochondrial respiration, as well as dysfunctional Ca2+ release-activated Ca2+ (CRAC) channels. Perturbation of CRAC channel function dampened calcium influx into CTLs, delayed CTL degranulation, and lowered the frequency of sublethal hits (i.e., additive cytotoxicity) delivered to the target cell. Thus, CRAC channel activity controls both individual contact efficacy and CTL cooperativity required for serial killing of target cells. The multistep analysis of CTL effector responses in 3D coculture will facilitate the identification of immune-suppressive mechanisms and guide the rational design of targeted intervention strategies to restore CTL effector function.
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Affiliation(s)
- Jeroen Slaats
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Cindy E Dieteren
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands.,Protinhi Therapeutics, Noviotech Campus, Nijmegen, the Netherlands
| | - Esther Wagena
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Louis Wolf
- Microscopic Imaging Center, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Tonke K Raaijmakers
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands.,Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jeroen A van der Laak
- Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Carl G Figdor
- Department of Tumor Immunology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bettina Weigelin
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Peter Friedl
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands. .,Department of Genitourinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Cancer Genomics Center, Utrecht, the Netherlands
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West SJ, Kodakandla G, Wang Q, Tewari R, Zhu MX, Boehning D, Akimzhanov AM. S-acylation of Orai1 regulates store-operated Ca2+ entry. J Cell Sci 2021; 135:269207. [PMID: 34156466 DOI: 10.1242/jcs.258579] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
Store-operated Ca2+ entry is a central component of intracellular Ca2+ signaling pathways. The Ca2+ release-activated channel (CRAC) mediates store-operated Ca2+ entry in many different cell types. The CRAC channel is composed of the plasma membrane (PM)-localized Orai1 channel and endoplasmic reticulum (ER)-localized STIM1 Ca2+ sensor. Upon ER Ca2+ store depletion, Orai1 and STIM1 form complexes at ER-PM junctions, leading to the formation of activated CRAC channels. Although the importance of CRAC channels is well described, the underlying mechanisms that regulate the recruitment of Orai1 to ER-PM junctions are not fully understood. Here, we describe the rapid and transient S-acylation of Orai1. Using biochemical approaches, we show that Orai1 is rapidly S-acylated at cysteine 143 upon ER Ca2+ store depletion. Importantly, S-acylation of cysteine 143 is required for Orai1-mediated Ca2+ entry and recruitment to STIM1 puncta. We conclude that store depletion-induced S-acylation of Orai1 is necessary for recruitment to ER-PM junctions, subsequent binding to STIM1 and channel activation.
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Affiliation(s)
- Savannah J West
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Goutham Kodakandla
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Qioachu Wang
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ritika Tewari
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Michael X Zhu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Darren Boehning
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Askar M Akimzhanov
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Dubois C, Kondratska K, Kondratskyi A, Morabito A, Mesilmany L, Farfariello V, Toillon RA, Ziental Gelus N, Laurenge E, Vanden Abeele F, Lemonnier L, Prevarskaya N. ORAI3 silencing alters cell proliferation and promotes mitotic catastrophe and apoptosis in pancreatic adenocarcinoma. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2021; 1868:119023. [PMID: 33798603 DOI: 10.1016/j.bbamcr.2021.119023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 12/24/2022]
Abstract
Changes in cytosolic free Ca2+ concentration play a central role in many fundamental cellular processes including muscle contraction, neurotransmission, cell proliferation, differentiation, gene transcription and cell death. Many of these processes are known to be regulated by store-operated calcium channels (SOCs), among which ORAI1 is the most studied in cancer cells, leaving the role of other ORAI channels yet inadequately addressed. Here we demonstrate that ORAI3 channels are expressed in both normal (HPDE) and pancreatic ductal adenocarcinoma (PDAC) cell lines, where they form functional channels, their knockdown affecting store operated calcium entry (SOCE). More specifically, ORAI3 silencing increased SOCE in PDAC cell lines, while decreasing SOCE in normal pancreatic cell line. We also show the role of ORAI3 in proliferation, cell cycle, viability, mitotic catastrophe and cell death. Finally, we demonstrate that ORAI3 silencing impairs pancreatic tumor growth and induces cell death in vivo, suggesting that ORAI3 could represent a potential therapeutic target in PDAC treatment.
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Affiliation(s)
- Charlotte Dubois
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Kateryna Kondratska
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Artem Kondratskyi
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Angela Morabito
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Lina Mesilmany
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Valerio Farfariello
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | | | | | - Emilie Laurenge
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Fabien Vanden Abeele
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Loic Lemonnier
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France
| | - Natalia Prevarskaya
- Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, 59000 Lille, France.
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48
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Sánchez-Collado J, López JJ, Rosado JA. The Orai1-AC8 Interplay: How Breast Cancer Cells Escape from Orai1 Channel Inactivation. Cells 2021; 10:1308. [PMID: 34070268 PMCID: PMC8225208 DOI: 10.3390/cells10061308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 11/16/2022] Open
Abstract
The interplay between the Ca2+-sensitive adenylyl cyclase 8 (AC8) and Orai1 channels plays an important role both in the activation of the cAMP/PKA signaling and the modulation of Orai1-dependent Ca2+ signals. AC8 interacts with a N-terminal region that is exclusive to the Orai1 long variant, Orai1α. The interaction between both proteins allows the Ca2+ that enters the cell through Orai1α to activate the generation of cAMP by AC8. Subsequent PKA activation results in Orai1α inactivation by phosphorylation at serine-34, thus shaping Orai1-mediated cellular functions. In breast cancer cells, AC8 plays a relevant role supporting a variety of cancer hallmarks, including proliferation and migration. Breast cancer cells overexpress AC8, which shifts the AC8-Orai1 stoichiometry in favor of the former and leads to the impairment of PKA-dependent Orai1α inactivation. This mechanism contributes to the enhanced SOCE observed in triple-negative breast cancer cells. This review summarizes the functional interaction between AC8 and Orai1α in normal and breast cancer cells and its relevance for different cancer features.
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Affiliation(s)
| | - José J. López
- Cellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain;
| | - Juan A. Rosado
- Cellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain;
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49
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Maksoud MJE, Tellios V, Xiang YY, Lu WY. Nitric oxide displays a biphasic effect on calcium dynamics in microglia. Nitric Oxide 2021; 108:28-39. [PMID: 33418057 DOI: 10.1016/j.niox.2021.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/11/2020] [Accepted: 01/01/2021] [Indexed: 01/13/2023]
Abstract
Calcium is a critical secondary messenger in microglia. In response to inflammation, microglia mobilize intracellular calcium and increase the expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO). This study set to explore whether NO regulates intracellular calcium dynamics through transient receptor potential (TRP) channels in primary wildtype (WT) and iNOS knockout (iNOS-/-) microglia, and the BV2 microglial cell line using calcium imaging and voltage-clamp recordings. Our results demonstrated that application of the NO-donor SNAP induced a biphasic calcium response in naïve murine microglia. Specifically, phase I was characterized by a rapid decline in calcium influx that was attenuated by pretreatment of the store operated calcium channel (SOCC) inhibitor 2APB, while phase II presented as a slow calcium influx that was abolished by pretreatment with the TRP vanilloid type 2 (TRPV2) channel inhibitor tranilast. Importantly, in the presence of a protein kinase G (PKG) inhibitor, the SNAP-mediated calcium decline in phase I persisted while the calcium influx in phase II was abolished. Application of thapsigargin to activate SOCCs caused a calcium influx through a nonselective cation conductance in BV2 microglia, which was abruptly attenuated by SNAP. Importantly, iNOS-/- microglia displayed a significantly larger calcium influx though SOCCs while expressing less stromal interaction molecule 1, Orai1, and TRP canonical type 1 and 3 mRNA, when compared to WT microglia. Together, these results demonstrate that NO signaling restricts calcium influx through SOCCs independent of PKG signaling and increases calcium influx through TRPV2 channels in a PKG-dependent mechanism in microglia.
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Affiliation(s)
- Matthew J E Maksoud
- Graduate Program of Neuroscience, The University of Western Ontario, Canada; Robarts Research Institute, The University of Western Ontario, Canada.
| | - Vasiliki Tellios
- Graduate Program of Neuroscience, The University of Western Ontario, Canada; Robarts Research Institute, The University of Western Ontario, Canada.
| | - Yun-Yan Xiang
- Robarts Research Institute, The University of Western Ontario, Canada.
| | - Wei-Yang Lu
- Graduate Program of Neuroscience, The University of Western Ontario, Canada; Robarts Research Institute, The University of Western Ontario, Canada; Department of Physiology and Pharmacology, University of Western Ontario, Canada.
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50
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Yu F, Agrebi N, Mackeh R, Abouhazima K, KhudaBakhsh K, Adeli M, Lo B, Hassan A, Machaca K. Novel ORAI1 Mutation Disrupts Channel Trafficking Resulting in Combined Immunodeficiency. J Clin Immunol 2021; 41:1004-1015. [PMID: 33650027 PMCID: PMC8249264 DOI: 10.1007/s10875-021-01004-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/19/2021] [Indexed: 11/23/2022]
Abstract
Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient’s lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.
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Affiliation(s)
- Fang Yu
- Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar.,Calcium Signaling Group, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Nourhen Agrebi
- Translational Medicine Department, Sidra Medicine, Doha, Qatar
| | - Rafah Mackeh
- Translational Medicine Department, Sidra Medicine, Doha, Qatar
| | - Khaled Abouhazima
- Pediatric Gastroenterology, Sidra Medicine, Education City, Doha, Qatar
| | | | - Mehdi Adeli
- Pediatric Allergy and Immunology Department, Sidra Medicine, Education City, Doha, Qatar
| | - Bernice Lo
- Translational Medicine Department, Sidra Medicine, Doha, Qatar. .,College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
| | - Amel Hassan
- Pediatric Allergy and Immunology Department, Sidra Medicine, Education City, Doha, Qatar.
| | - Khaled Machaca
- Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar. .,Calcium Signaling Group, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar.
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