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1
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Ivanova A, Atakpa-Adaji P, Rao S, Marti-Solano M, Taylor CW. Dual regulation of IP 3 receptors by IP 3 and PIP 2 controls the transition from local to global Ca 2+ signals. Mol Cell 2024; 84:3997-4015.e7. [PMID: 39366376 DOI: 10.1016/j.molcel.2024.09.009] [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: 12/14/2023] [Revised: 07/11/2024] [Accepted: 09/08/2024] [Indexed: 10/06/2024]
Abstract
The spatial organization of inositol 1,4,5-trisphosphate (IP3)-evoked Ca2+ signals underlies their versatility. Low stimulus intensities evoke Ca2+ puffs, localized Ca2+ signals arising from a few IP3 receptors (IP3Rs) within a cluster tethered beneath the plasma membrane. More intense stimulation evokes global Ca2+ signals. Ca2+ signals propagate regeneratively as the Ca2+ released stimulates more IP3Rs. How is this potentially explosive mechanism constrained to allow local Ca2+ signaling? We developed methods that allow IP3 produced after G-protein coupled receptor (GPCR) activation to be intercepted and replaced by flash photolysis of a caged analog of IP3. We find that phosphatidylinositol 4,5-bisphosphate (PIP2) primes IP3Rs to respond by partially occupying their IP3-binding sites. As GPCRs stimulate IP3 formation, they also deplete PIP2, relieving the priming stimulus. Loss of PIP2 resets IP3R sensitivity and delays the transition from local to global Ca2+ signals. Dual regulation of IP3Rs by PIP2 and IP3 through GPCRs controls the transition from local to global Ca2+ signals.
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Affiliation(s)
- Adelina Ivanova
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
| | - Peace Atakpa-Adaji
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
| | - Shanlin Rao
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
| | - Maria Marti-Solano
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
| | - Colin W Taylor
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
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2
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Ismatullah H, Jabeen I, Kiani YS. Structural and functional insight into a new emerging target IP 3R in cancer. J Biomol Struct Dyn 2024; 42:2170-2196. [PMID: 37070253 DOI: 10.1080/07391102.2023.2201332] [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: 01/27/2023] [Accepted: 04/05/2023] [Indexed: 04/19/2023]
Abstract
Calcium signaling has been identified as an important phenomenon in a plethora of cellular processes. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ER-residing intracellular calcium (Ca2+) release channels responsible for cell bioenergetics by transferring calcium from the ER to the mitochondria. The recent availability of full-length IP3R channel structure has enabled the researchers to design the IP3 competitive ligands and reveal the channel gating mechanism by elucidating the conformational changes induced by ligands. However, limited knowledge is available for IP3R antagonists and the exact mechanism of action of these antagonists within a tumorigenic environment of a cell. Here in this review a summarized information about the role of IP3R in cell proliferation and apoptosis has been discussed. Moreover, structure and gating mechanism of IP3R in the presence of antagonists have been provided in this review. Additionally, compelling information about ligand-based studies (both agonists and antagonists) has been discussed. The shortcomings of these studies and the challenges toward the design of potent IP3R modulators have also been provided in this review. However, the conformational changes induced by antagonists for channel gating mechanism still display some major drawbacks that need to be addressed. However, the design, synthesis and availability of isoform-specific antagonists is a rather challenging one due to intra-structural similarity within the binding domain of each isoform. HighlightsThe intricate complexity of IP3R's in cellular processes declares them an important target whereby, the recently solved structure depicts the receptor's potential involvement in a complex network of processes spanning from cell proliferation to cell death.Pharmacological inhibition of IP3R attenuates the proliferation or invasiveness of cancers, thus inducing necrotic cell death.Despite significant advancements, there is a tremendous need to design new potential hits to target IP3R, based upon 3D structural features and pharmacophoric patterns.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Humaira Ismatullah
- Department of Sciences, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Ishrat Jabeen
- Department of Sciences, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Yusra Sajid Kiani
- Department of Sciences, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
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3
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Moccia F, Fiorio Pla A, Lim D, Lodola F, Gerbino A. Intracellular Ca 2+ signalling: unexpected new roles for the usual suspect. Front Physiol 2023; 14:1210085. [PMID: 37576340 PMCID: PMC10413985 DOI: 10.3389/fphys.2023.1210085] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/18/2023] [Indexed: 08/15/2023] Open
Abstract
Cytosolic Ca2+ signals are organized in complex spatial and temporal patterns that underlie their unique ability to regulate multiple cellular functions. Changes in intracellular Ca2+ concentration ([Ca2+]i) are finely tuned by the concerted interaction of membrane receptors and ion channels that introduce Ca2+ into the cytosol, Ca2+-dependent sensors and effectors that translate the elevation in [Ca2+]i into a biological output, and Ca2+-clearing mechanisms that return the [Ca2+]i to pre-stimulation levels and prevent cytotoxic Ca2+ overload. The assortment of the Ca2+ handling machinery varies among different cell types to generate intracellular Ca2+ signals that are selectively tailored to subserve specific functions. The advent of novel high-speed, 2D and 3D time-lapse imaging techniques, single-wavelength and genetic Ca2+ indicators, as well as the development of novel genetic engineering tools to manipulate single cells and whole animals, has shed novel light on the regulation of cellular activity by the Ca2+ handling machinery. A symposium organized within the framework of the 72nd Annual Meeting of the Italian Society of Physiology, held in Bari on 14-16th September 2022, has recently addressed many of the unexpected mechanisms whereby intracellular Ca2+ signalling regulates cellular fate in healthy and disease states. Herein, we present a report of this symposium, in which the following emerging topics were discussed: 1) Regulation of water reabsorption in the kidney by lysosomal Ca2+ release through Transient Receptor Potential Mucolipin 1 (TRPML1); 2) Endoplasmic reticulum-to-mitochondria Ca2+ transfer in Alzheimer's disease-related astroglial dysfunction; 3) The non-canonical role of TRP Melastatin 8 (TRPM8) as a Rap1A inhibitor in the definition of some cancer hallmarks; and 4) Non-genetic optical stimulation of Ca2+ signals in the cardiovascular system.
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Affiliation(s)
- Francesco Moccia
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Dmitry Lim
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale “Amedeo Avogadro”, Novara, Italy
| | - Francesco Lodola
- Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy
- Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Milan, Italy
| | - Andrea Gerbino
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
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4
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Friedhoff VN, Lindner B, Falcke M. Modeling IP 3-induced Ca 2+ signaling based on its interspike interval statistics. Biophys J 2023; 122:2818-2831. [PMID: 37312455 PMCID: PMC10398346 DOI: 10.1016/j.bpj.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/24/2023] [Accepted: 06/06/2023] [Indexed: 06/15/2023] Open
Abstract
Inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ signaling is a second messenger system used by almost all eukaryotic cells. Recent research demonstrated randomness of Ca2+ signaling on all structural levels. We compile eight general properties of Ca2+ spiking common to all cell types investigated and suggest a theory of Ca2+ spiking starting from the random behavior of IP3 receptor channel clusters mediating the release of Ca2+ from the endoplasmic reticulum capturing all general properties and pathway-specific behavior. Spike generation begins after the absolute refractory period of the previous spike. According to its hierarchical spreading from initiating channel openings to cell level, we describe it as a first passage process from none to all clusters open while the cell recovers from the inhibition which terminated the previous spike. Our theory reproduces the exponential stimulation response relation of the average interspike interval Tav and its robustness properties, random spike timing with a linear moment relation between Tav and the interspike interval SD and its robustness properties, sensitive dependency of Tav on diffusion properties, and nonoscillatory local dynamics. We explain large cell variability of Tav observed in experiments by variability of channel cluster coupling by Ca2+-induced Ca2+ release, the number of clusters, and IP3 pathway component expression levels. We predict the relation between puff probability and agonist concentration and [IP3] and agonist concentration. Differences of spike behavior between cell types and stimulating agonists are explained by the different types of negative feedback terminating spikes. In summary, the hierarchical random character of spike generation explains all of the identified general properties.
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Affiliation(s)
- Victor Nicolai Friedhoff
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Physics, Humboldt University, Berlin, Germany
| | - Benjamin Lindner
- Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany; Department of Physics, Humboldt University, Berlin, Germany
| | - Martin Falcke
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Physics, Humboldt University, Berlin, Germany.
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5
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King DR, Sedovy MW, Eaton X, Dunaway LS, Good ME, Isakson BE, Johnstone SR. Cell-To-Cell Communication in the Resistance Vasculature. Compr Physiol 2022; 12:3833-3867. [PMID: 35959755 DOI: 10.1002/cphy.c210040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The arterial vasculature can be divided into large conduit arteries, intermediate contractile arteries, resistance arteries, arterioles, and capillaries. Resistance arteries and arterioles primarily function to control systemic blood pressure. The resistance arteries are composed of a layer of endothelial cells oriented parallel to the direction of blood flow, which are separated by a matrix layer termed the internal elastic lamina from several layers of smooth muscle cells oriented perpendicular to the direction of blood flow. Cells within the vessel walls communicate in a homocellular and heterocellular fashion to govern luminal diameter, arterial resistance, and blood pressure. At rest, potassium currents govern the basal state of endothelial and smooth muscle cells. Multiple stimuli can elicit rises in intracellular calcium levels in either endothelial cells or smooth muscle cells, sourced from intracellular stores such as the endoplasmic reticulum or the extracellular space. In general, activation of endothelial cells results in the production of a vasodilatory signal, usually in the form of nitric oxide or endothelial-derived hyperpolarization. Conversely, activation of smooth muscle cells results in a vasoconstriction response through smooth muscle cell contraction. © 2022 American Physiological Society. Compr Physiol 12: 1-35, 2022.
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Affiliation(s)
- D Ryan King
- Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Vascular and Heart Research, Virginia Tech, Roanoke, Virginia, USA
| | - Meghan W Sedovy
- Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Vascular and Heart Research, Virginia Tech, Roanoke, Virginia, USA.,Translational Biology, Medicine, and Health Graduate Program, Virginia Tech, Blacksburg, Virginia, USA
| | - Xinyan Eaton
- Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Vascular and Heart Research, Virginia Tech, Roanoke, Virginia, USA
| | - Luke S Dunaway
- Robert M. Berne Cardiovascular Research Centre, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Miranda E Good
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Centre, University of Virginia School of Medicine, Charlottesville, Virginia, USA.,Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Scott R Johnstone
- Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Vascular and Heart Research, Virginia Tech, Roanoke, Virginia, USA.,Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA
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6
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KRAP tethers IP 3 receptors to actin and licenses them to evoke cytosolic Ca 2+ signals. Nat Commun 2021; 12:4514. [PMID: 34301929 PMCID: PMC8302619 DOI: 10.1038/s41467-021-24739-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 07/01/2021] [Indexed: 02/06/2023] Open
Abstract
Regulation of IP3 receptors (IP3Rs) by IP3 and Ca2+ allows regenerative Ca2+ signals, the smallest being Ca2+ puffs, which arise from coordinated openings of a few clustered IP3Rs. Cells express thousands of mostly mobile IP3Rs, yet Ca2+ puffs occur at a few immobile IP3R clusters. By imaging cells with endogenous IP3Rs tagged with EGFP, we show that KRas-induced actin-interacting protein (KRAP) tethers IP3Rs to actin beneath the plasma membrane. Loss of KRAP abolishes Ca2+ puffs and the global increases in cytosolic Ca2+ concentration evoked by more intense stimulation. Over-expressing KRAP immobilizes additional IP3R clusters and results in more Ca2+ puffs and larger global Ca2+ signals. Endogenous KRAP determines which IP3Rs will respond: it tethers IP3R clusters to actin alongside sites where store-operated Ca2+ entry occurs, licenses IP3Rs to evoke Ca2+ puffs and global cytosolic Ca2+ signals, implicates the actin cytoskeleton in IP3R regulation and may allow local activation of Ca2+ entry.
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7
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Gambardella J, Morelli MB, Wang X, Castellanos V, Mone P, Santulli G. The discovery and development of IP3 receptor modulators: an update. Expert Opin Drug Discov 2021; 16:709-718. [PMID: 33356639 DOI: 10.1080/17460441.2021.1858792] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Introduction: Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular calcium (Ca2+) release channels located on the endoplasmic/sarcoplasmic reticulum. The availability of the structure of the ligand-binding domain of IP3Rs has enabled the design of compatible ligands, but the limiting step remains their actual effectiveness in a biological context.Areas covered: This article summarizes the compelling literature on both agonists and antagonists targeting IP3Rs, emphasizing their strengths and limitations. The main challenges toward the discovery and development of IP3 receptor modulators are also described.Expert opinion: Despite significant progress in recent years, the pharmacology of IP3R still has major drawbacks, especially concerning the availability of specific antag onists. Moreover, drugs specifically targeting the three different subtypes of IP3R are especially needed.
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Affiliation(s)
- Jessica Gambardella
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, Montefiore University Hospital, New York City, USA.,Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism, Einstein-Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, USA.,Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy.,International Translational Research and Medical Education (ITME), Naples, Italy
| | - Marco B Morelli
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, Montefiore University Hospital, New York City, USA.,Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism, Einstein-Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, USA
| | - Xujun Wang
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, Montefiore University Hospital, New York City, USA
| | - Vanessa Castellanos
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, Montefiore University Hospital, New York City, USA
| | - Pasquale Mone
- University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Gaetano Santulli
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, Montefiore University Hospital, New York City, USA.,Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism, Einstein-Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, USA.,Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy.,International Translational Research and Medical Education (ITME), Naples, Italy
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8
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Atakpa-Adaji P, Thillaiappan NB, Taylor CW. IP3 receptors and their intimate liaisons. CURRENT OPINION IN PHYSIOLOGY 2020. [DOI: 10.1016/j.cophys.2020.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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9
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Vais H, Wang M, Mallilankaraman K, Payne R, McKennan C, Lock JT, Spruce LA, Fiest C, Chan MYL, Parker I, Seeholzer SH, Foskett JK, Mak DOD. ER-luminal [Ca 2+] regulation of InsP 3 receptor gating mediated by an ER-luminal peripheral Ca 2+-binding protein. eLife 2020; 9:e53531. [PMID: 32420875 PMCID: PMC7259957 DOI: 10.7554/elife.53531] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 05/15/2020] [Indexed: 12/17/2022] Open
Abstract
Modulating cytoplasmic Ca2+ concentration ([Ca2+]i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca2+ concentration ([Ca2+]ER) is poorly understood and controversial. We discovered that the InsP3R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the channel in the presence of high, physiological [Ca2+]ER. The widely-expressed Ca2+-binding protein annexin A1 (ANXA1) is present in the nuclear envelope lumen and, through interaction with a luminal region of the channel, can modify high-[Ca2+]ER inhibition of InsP3R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP3-mediated Ca2+ signaling events. Thus, [Ca2+]ER is a major regulator of InsP3R channel activity and InsP3R-mediated [Ca2+]i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca2+-binding protein, likely ANXA1.
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Affiliation(s)
- Horia Vais
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Min Wang
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Karthik Mallilankaraman
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Riley Payne
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Chris McKennan
- Department of Statistics, University of PittsburghPittsburghUnited States
| | - Jeffrey T Lock
- Department of Neurobiology and Behavior, University of CaliforniaIrvineUnited States
| | - Lynn A Spruce
- Proteomics Core Facility, The Children’s Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Carly Fiest
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Matthew Yan-lok Chan
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Ian Parker
- Department of Neurobiology and Behavior, University of CaliforniaIrvineUnited States
- Department of Physiology and Biophysics, University of CaliforniaIrvineUnited States
| | - Steven H Seeholzer
- Proteomics Core Facility, The Children’s Hospital of PhiladelphiaPhiladelphiaUnited States
| | - J Kevin Foskett
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Don-On Daniel Mak
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
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10
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Lock JT, Parker I. IP 3 mediated global Ca 2+ signals arise through two temporally and spatially distinct modes of Ca 2+ release. eLife 2020; 9:e55008. [PMID: 32396066 PMCID: PMC7253181 DOI: 10.7554/elife.55008] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022] Open
Abstract
The 'building-block' model of inositol trisphosphate (IP3)-mediated Ca2+ liberation posits that cell-wide cytosolic Ca2+ signals arise through coordinated activation of localized Ca2+ puffs generated by stationary clusters of IP3 receptors (IP3Rs). Here, we revise this hypothesis, applying fluctuation analysis to resolve Ca2+ signals otherwise obscured during large Ca2+ elevations. We find the rising phase of global Ca2+ signals is punctuated by a flurry of puffs, which terminate before the peak by a mechanism involving partial ER Ca2+ depletion. The continuing rise in Ca2+, and persistence of global signals even when puffs are absent, reveal a second mode of spatiotemporally diffuse Ca2+ signaling. Puffs make only small, transient contributions to global Ca2+ signals, which are sustained by diffuse release of Ca2+ through a functionally distinct process. These two modes of IP3-mediated Ca2+ liberation have important implications for downstream signaling, imparting spatial and kinetic specificity to Ca2+-dependent effector functions and Ca2+ transport.
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Affiliation(s)
- Jeffrey T Lock
- Department of Neurobiology & Behavior, UC IrvineIrvineUnited States
| | - Ian Parker
- Department of Neurobiology & Behavior, UC IrvineIrvineUnited States
- Department of Physiology & Biophysics, UC IrvineIrvineUnited States
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11
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Cui WQ, Wang ST, Pan D, Chang B, Sang LX. Caffeine and its main targets of colorectal cancer. World J Gastrointest Oncol 2020; 12:149-172. [PMID: 32104547 PMCID: PMC7031145 DOI: 10.4251/wjgo.v12.i2.149] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/25/2019] [Accepted: 11/13/2019] [Indexed: 02/05/2023] Open
Abstract
Caffeine is a purine alkaloid and is widely consumed in coffee, soda, tea, chocolate and energy drinks. To date, a growing number of studies have indicated that caffeine is associated with many diseases including colorectal cancer. Caffeine exerts its biological activity through binding to adenosine receptors, inhibiting phosphodiesterases, sensitizing calcium channels, antagonizing gamma-aminobutyric acid receptors and stimulating adrenal hormones. Some studies have indicated that caffeine can interact with signaling pathways such as transforming growth factor β, phosphoinositide-3-kinase/AKT/mammalian target of rapamycin and mitogen-activated protein kinase pathways through which caffeine can play an important role in colorectal cancer pathogenesis, metastasis and prognosis. Moreover, caffeine can act as a general antioxidant that protects cells from oxidative stress and also as a regulatory factor of the cell cycle that modulates the DNA repair system. Additionally, as for intestinal homeostasis, through the interaction with receptors and cytokines, caffeine can modulate the immune system mediating its effects on T lymphocytes, B lymphocytes, natural killer cells and macrophages. Furthermore, caffeine can not only directly inhibit species in the gut microbiome, such as Escherichia coli and Candida albicans but also can indirectly exert inhibition by increasing the effects of other antimicrobial drugs. This review summarizes the association between colorectal cancer and caffeine that is being currently studied.
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Affiliation(s)
- Wen-Qi Cui
- Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- China Medical University 101K class 87, Shenyang 110001, Liaoning Province, China
| | - Shi-Tong Wang
- Department of Cardiovascular Ultrasound, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- China Medical University 101K class 87, Shenyang 110001, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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12
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Powell J, Falcke M, Skupin A, Bellamy TC, Kypraios T, Thul R. A Statistical View on Calcium Oscillations. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1131:799-826. [PMID: 31646535 DOI: 10.1007/978-3-030-12457-1_32] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Transient rises and falls of the intracellular calcium concentration have been observed in numerous cell types and under a plethora of conditions. There is now a growing body of evidence that these whole-cell calcium oscillations are stochastic, which poses a significant challenge for modelling. In this review, we take a closer look at recently developed statistical approaches to calcium oscillations. These models describe the timing of whole-cell calcium spikes, yet their parametrisations reflect subcellular processes. We show how non-stationary calcium spike sequences, which e.g. occur during slow depletion of intracellular calcium stores or in the presence of time-dependent stimulation, can be analysed with the help of so-called intensity functions. By utilising Bayesian concepts, we demonstrate how values of key parameters of the statistical model can be inferred from single cell calcium spike sequences and illustrate what information whole-cell statistical models can provide about the subcellular mechanistic processes that drive calcium oscillations. In particular, we find that the interspike interval distribution of HEK293 cells under constant stimulation is captured by a Gamma distribution.
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Affiliation(s)
- Jake Powell
- Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, UK
| | - Martin Falcke
- Max Delbrück Centre for Molecular Medicine, Berlin, Germany.,Department of Physics, Humboldt University, Berlin, Germany
| | - Alexander Skupin
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg.,National Biomedical Computation Resource, University California San Diego, La Jolla, CA, USA
| | - Tomas C Bellamy
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Theodore Kypraios
- Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, UK
| | - Rüdiger Thul
- Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, UK.
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13
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Egorova PA, Bezprozvanny IB. Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2. Neurotherapeutics 2019; 16:1050-1073. [PMID: 31435879 PMCID: PMC6985344 DOI: 10.1007/s13311-019-00777-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.
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Affiliation(s)
- Polina A Egorova
- Laboratory of Molecular Neurodegeneration, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, 195251, Russia
| | - Ilya B Bezprozvanny
- Laboratory of Molecular Neurodegeneration, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, 195251, Russia.
- Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, ND12.200, Dallas, Texas, 75390, USA.
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14
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Taylor CW, Machaca K. IP3 receptors and store-operated Ca2+ entry: a license to fill. Curr Opin Cell Biol 2019; 57:1-7. [DOI: 10.1016/j.ceb.2018.10.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/05/2018] [Indexed: 10/28/2022]
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15
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Prole DL, Taylor CW. Structure and Function of IP 3 Receptors. Cold Spring Harb Perspect Biol 2019; 11:cshperspect.a035063. [PMID: 30745293 DOI: 10.1101/cshperspect.a035063] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inositol 1,4,5-trisphosphate receptors (IP3Rs), by releasing Ca2+ from the endoplasmic reticulum (ER) of animal cells, allow Ca2+ to be redistributed from the ER to the cytosol or other organelles, and they initiate store-operated Ca2+ entry (SOCE). For all three IP3R subtypes, binding of IP3 primes them to bind Ca2+, which then triggers channel opening. We are now close to understanding the structural basis of IP3R activation. Ca2+-induced Ca2+ release regulated by IP3 allows IP3Rs to regeneratively propagate Ca2+ signals. The smallest of these regenerative events is a Ca2+ puff, which arises from the nearly simultaneous opening of a small cluster of IP3Rs. Ca2+ puffs are the basic building blocks for all IP3-evoked Ca2+ signals, but only some IP3 clusters, namely those parked alongside the ER-plasma membrane junctions where SOCE occurs, are licensed to respond. The location of these licensed IP3Rs may allow them to selectively regulate SOCE.
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Affiliation(s)
- David L Prole
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom
| | - Colin W Taylor
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom
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16
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Lock JT, Smith IF, Parker I. Spatial-temporal patterning of Ca 2+ signals by the subcellular distribution of IP 3 and IP 3 receptors. Semin Cell Dev Biol 2019; 94:3-10. [PMID: 30703557 DOI: 10.1016/j.semcdb.2019.01.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/17/2019] [Accepted: 01/22/2019] [Indexed: 12/25/2022]
Abstract
The patterning of cytosolic Ca2+ signals in space and time underlies their ubiquitous ability to specifically regulate numerous cellular processes. Signals mediated by liberation of Ca2+ sequestered in the endoplasmic reticulum (ER) through inositol trisphosphate receptor (IP3R) channels constitute a hierarchy of events; ranging from openings of individual IP3 channels, through the concerted openings of several clustered IP3Rs to generate local Ca2+ puffs, to global Ca2+ waves and oscillations that engulf the entire cell. Here, we review recent progress in elucidating how this hierarchy is shaped by an interplay between the functional gating properties of IP3Rs and their spatial distribution within the cell. We focus in particular on the subset of IP3Rs that are organized in stationary clusters and are endowed with the ability to preferentially liberate Ca2+.
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Affiliation(s)
- Jeffrey T Lock
- Department of Neurobiology & Behavior, UC Irvine, Irvine, CA, USA.
| | - Ian F Smith
- Department of Neurobiology & Behavior, UC Irvine, Irvine, CA, USA
| | - Ian Parker
- Department of Neurobiology & Behavior, UC Irvine, Irvine, CA, USA; Department of Physiology & Biophysics, UC Irvine, Irvine, CA, USA
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17
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Endolysosomal Ca 2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind! Cancers (Basel) 2018; 11:cancers11010027. [PMID: 30591696 PMCID: PMC6356888 DOI: 10.3390/cancers11010027] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 12/21/2018] [Accepted: 12/21/2018] [Indexed: 12/22/2022] Open
Abstract
The acidic vesicles of the endolysosomal (EL) system are emerging as an intracellular Ca2+ store implicated in the regulation of multiple cellular functions. The EL Ca2+ store releases Ca2+ through a variety of Ca2+-permeable channels, including Transient Receptor Potential (TRP) Mucolipin 1-3 (TRPML1-3) and two-pore channels 1-2 (TPC1-2), whereas EL Ca2+ refilling is sustained by the proton gradient across the EL membrane and/or by the endoplasmic reticulum (ER). EL Ca2+ signals may be either spatially restricted to control vesicle trafficking, autophagy and membrane repair or may be amplified into a global Ca2+ signal through the Ca2+-dependent recruitment of ER-embedded channels. Emerging evidence suggested that nicotinic acid adenine dinucleotide phosphate (NAADP)-gated TPCs sustain multiple cancer hallmarks, such as migration, invasiveness and angiogenesis. Herein, we first survey the EL Ca2+ refilling and release mechanisms and then focus on the oncogenic role of EL Ca2+ signaling. While the evidence in favor of TRPML1 involvement in neoplastic transformation is yet to be clearly provided, TPCs are emerging as an alternative target for anticancer therapies.
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18
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Lock JT, Alzayady KJ, Yule DI, Parker I. All three IP 3 receptor isoforms generate Ca 2+ puffs that display similar characteristics. Sci Signal 2018; 11:11/561/eaau0344. [PMID: 30563861 DOI: 10.1126/scisignal.aau0344] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inositol 1,4,5-trisphosphate (IP3) evokes Ca2+ release through IP3 receptors (IP3Rs) to generate both local Ca2+ puffs arising from concerted openings of clustered IP3Rs and cell-wide Ca2+ waves. Imaging Ca2+ puffs with single-channel resolution yields information on the localization and properties of native IP3Rs in intact cells, but interpretation has been complicated because cells express varying proportions of three structurally and functionally distinct isoforms of IP3Rs. Here, we used TIRF and light-sheet microscopy to image Ca2+ puffs in HEK-293 cell lines generated by CRISPR-Cas9 technology to express exclusively IP3R type 1, 2, or 3. Photorelease of the IP3 analog i-IP3 in all three cell lines evoked puffs with largely similar mean amplitudes, temporal characteristics, and spatial extents. Moreover, the single-channel Ca2+ flux was similar among isoforms, indicating that clusters of different IP3R isoforms contain comparable numbers of active channels. Our results show that all three IP3R isoforms cluster to generate local Ca2+ puffs and, contrary to findings of divergent properties from in vitro electrophysiological studies, display similar conductances and gating kinetics in intact cells.
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Affiliation(s)
- Jeffrey T Lock
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
| | - Kamil J Alzayady
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA
| | - David I Yule
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA
| | - Ian Parker
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.,Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA
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19
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Thillaiappan NB, Chakraborty P, Hasan G, Taylor CW. IP 3 receptors and Ca 2+ entry. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1866:1092-1100. [PMID: 30448464 DOI: 10.1016/j.bbamcr.2018.11.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 12/23/2022]
Abstract
Inositol 1,4,5-trisphosphate receptors (IP3R) are the most widely expressed intracellular Ca2+ release channels. Their activation by IP3 and Ca2+ allows Ca2+ to pass rapidly from the ER lumen to the cytosol. The resulting increase in cytosolic [Ca2+] may directly regulate cytosolic effectors or fuel Ca2+ uptake by other organelles, while the decrease in ER luminal [Ca2+] stimulates store-operated Ca2+ entry (SOCE). We are close to understanding the structural basis of both IP3R activation, and the interactions between the ER Ca2+-sensor, STIM, and the plasma membrane Ca2+ channel, Orai, that lead to SOCE. IP3Rs are the usual means through which extracellular stimuli, through ER Ca2+ release, stimulate SOCE. Here, we review evidence that the IP3Rs most likely to respond to IP3 are optimally placed to allow regulation of SOCE. We also consider evidence that IP3Rs may regulate SOCE downstream of their ability to deplete ER Ca2+ stores. Finally, we review evidence that IP3Rs in the plasma membrane can also directly mediate Ca2+ entry in some cells.
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Affiliation(s)
| | - Pragnya Chakraborty
- Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, United Kingdom; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore 560065, India
| | - Gaiti Hasan
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore 560065, India
| | - Colin W Taylor
- Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
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20
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Mataragka S, Taylor CW. All three IP 3 receptor subtypes generate Ca 2+ puffs, the universal building blocks of IP 3-evoked Ca 2+ signals. J Cell Sci 2018; 131:jcs.220848. [PMID: 30097556 PMCID: PMC6127726 DOI: 10.1242/jcs.220848] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/27/2018] [Indexed: 12/19/2022] Open
Abstract
All three subtypes of inositol 1,4,5-trisphosphate receptor (IP3R) are intracellular Ca2+ channels that are co-regulated by IP3 and Ca2+. This allows IP3Rs to evoke regenerative Ca2+ signals, the smallest of which are Ca2+ puffs that reflect the coordinated opening of a few clustered IP3Rs. We use total internal reflection microscopy (TIRF) microscopy to record Ca2+ signals in HEK cells expressing all three IP3R subtypes or a single native subtype. Ca2+ puffs are less frequent in cells expressing one IP3R subtype, commensurate with them expressing fewer IP3Rs than wild-type cells. However, all three IP3R subtypes generate broadly similar Ca2+ puffs with similar numbers of IP3Rs contributing to each. This suggests that IP3R clusters may be assembled by conserved mechanisms that generate similarly sized clusters across different IP3R expression levels. The Ca2+ puffs evoked by IP3R2 had slower kinetics and more prolonged durations, which may be due to IP3 binding with greater affinity to IP3R2. We conclude that Ca2+ puffs are the building blocks for the Ca2+ signals evoked by all IP3Rs. Summary: All IP3 receptor subtypes can generate Ca2+ puffs, suggesting that these coordinated openings of clustered IP3Rs are the building blocks of all IP3-evoked Ca2+ signals.
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Affiliation(s)
- Stefania Mataragka
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
| | - Colin W Taylor
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
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21
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Gonze D, Gérard C, Wacquier B, Woller A, Tosenberger A, Goldbeter A, Dupont G. Modeling-Based Investigation of the Effect of Noise in Cellular Systems. Front Mol Biosci 2018; 5:34. [PMID: 29707543 PMCID: PMC5907451 DOI: 10.3389/fmolb.2018.00034] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 03/26/2018] [Indexed: 12/14/2022] Open
Abstract
Noise is pervasive in cellular biology and inevitably affects the dynamics of cellular processes. Biological systems have developed regulatory mechanisms to ensure robustness with respect to noise or to take advantage of stochasticity. We review here, through a couple of selected examples, some insights on possible robustness factors and constructive roles of noise provided by computational modeling. In particular, we focus on (1) factors that likely contribute to the robustness of oscillatory processes such as the circadian clocks and the cell cycle, (2) how reliable coding/decoding of calcium-mediated signaling could be achieved in presence of noise and, in some cases, enhanced through stochastic resonance, and (3) how embryonic cell differentiation processes can exploit stochasticity to create heterogeneity in a population of identical cells.
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Affiliation(s)
- Didier Gonze
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
| | - Claude Gérard
- de Duve Institute (LPAD Group), Université Catholique de Louvain, Brussels, Belgium
| | - Benjamin Wacquier
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
| | - Aurore Woller
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
| | - Alen Tosenberger
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
| | - Albert Goldbeter
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
| | - Geneviève Dupont
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
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22
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Falcke M, Moein M, Tilūnaitė A, Thul R, Skupin A. On the phase space structure of IP 3 induced Ca 2+ signalling and concepts for predictive modeling. CHAOS (WOODBURY, N.Y.) 2018; 28:045115. [PMID: 31906671 DOI: 10.1063/1.5021073] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The correspondence between mathematical structures and experimental systems is the basis of the generalizability of results found with specific systems and is the basis of the predictive power of theoretical physics. While physicists have confidence in this correspondence, it is less recognized in cellular biophysics. On the one hand, the complex organization of cellular dynamics involving a plethora of interacting molecules and the basic observation of cell variability seem to question its possibility. The practical difficulties of deriving the equations describing cellular behaviour from first principles support these doubts. On the other hand, ignoring such a correspondence would severely limit the possibility of predictive quantitative theory in biophysics. Additionally, the existence of functional modules (like pathways) across cell types suggests also the existence of mathematical structures with comparable universality. Only a few cellular systems have been sufficiently investigated in a variety of cell types to follow up these basic questions. IP3 induced Ca2+signalling is one of them, and the mathematical structure corresponding to it is subject of ongoing discussion. We review the system's general properties observed in a variety of cell types. They are captured by a reaction diffusion system. We discuss the phase space structure of its local dynamics. The spiking regime corresponds to noisy excitability. Models focussing on different aspects can be derived starting from this phase space structure. We discuss how the initial assumptions on the set of stochastic variables and phase space structure shape the predictions of parameter dependencies of the mathematical models resulting from the derivation.
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Affiliation(s)
- Martin Falcke
- Max Delbrück Centre for Molecular Medicine, Robert Rössler Strasse 10, 13125 Berlin, Germany and Department of Physics, Humboldt University, Newtonstr. 15, 12489 Berlin, Germany
| | - Mahsa Moein
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Rue de Swing, Belval L-4367, Luxembourg
| | - Agne Tilūnaitė
- Systems Biology Laboratory, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Rüdiger Thul
- Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Alexander Skupin
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Rue de Swing, Belval L-4367, Luxembourg
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23
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Egorova PA, Bezprozvanny IB. Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. FEBS J 2018; 285:3547-3565. [PMID: 29253316 DOI: 10.1111/febs.14366] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 11/27/2017] [Accepted: 12/12/2017] [Indexed: 12/15/2022]
Abstract
The inositol 1,4,5-trisphosphate receptor (IP3 R) is an intracellular ion channel that mediates the release of calcium ions from the endoplasmic reticulum. It plays a role in basic biological functions, such as cell division, differentiation, fertilization and cell death, and is involved in developmental processes including learning, memory and behavior. Deregulation of neuronal calcium signaling results in disturbance of cell homeostasis, synaptic loss and dysfunction, eventually leading to cell death. Three IP3 R subtypes have been identified in mammalian cells and the predominant isoform in neurons is IP3 R type 1. Dysfunction of IP3 R type 1 may play a role in the pathogenesis of certain neurodegenerative diseases as enhanced activity of the IP3 R was observed in models of Huntington's disease, spinocerebellar ataxias and Alzheimer's disease. These results suggest that IP3 R-mediated signaling is a potential target for treatment of these disorders. In this review we discuss the structure, functions and regulation of the IP3 R in healthy neurons and in conditions of neurodegeneration.
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Affiliation(s)
- Polina A Egorova
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St Petersburg, Russia
| | - Ilya B Bezprozvanny
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St Petersburg, Russia.,Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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24
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Dynamic Ca 2+ imaging with a simplified lattice light-sheet microscope: A sideways view of subcellular Ca 2+ puffs. Cell Calcium 2017; 71:34-44. [PMID: 29604962 DOI: 10.1016/j.ceca.2017.11.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 11/29/2017] [Accepted: 11/30/2017] [Indexed: 11/24/2022]
Abstract
We describe the construction of a simplified, inexpensive lattice light-sheet microscope, and illustrate its use for imaging subcellular Ca2+ puffs evoked by photoreleased i-IP3 in cultured SH-SY5Y neuroblastoma cells loaded with the Ca2+ probe Cal520. The microscope provides sub-micron spatial resolution and enables recording of local Ca2+ transients in single-slice mode with a signal-to-noise ratio and temporal resolution (2ms) at least as good as confocal or total internal reflection microscopy. Signals arising from openings of individual IP3R channels are clearly resolved, as are stepwise changes in fluorescence reflecting openings and closings of individual channels during puffs. Moreover, by stepping the specimen through the light-sheet, the entire volume of a cell can be scanned within a few hundred ms. The ability to directly visualize a sideways (axial) section through cells directly reveals that IP3-evoked Ca2+ puffs originate at sites in very close (≤a few hundred nm) to the plasma membrane, suggesting they play a specific role in signaling to the membrane.
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