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1
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Zhu YQ, Wang LL, Li ZH, Qian SS, Xu Z, Zhang J, Song YH, Pan XS, Du N, Abou-Elnour A, Tay LJ, Zhang JR, Li MX, Shen YX, Huang Y. Acid-sensing ion channel 1a promotes alcohol-associated liver disease in mice via regulating endoplasmic reticulum autophagy. Acta Pharmacol Sin 2025; 46:989-1001. [PMID: 39592735 PMCID: PMC11950321 DOI: 10.1038/s41401-024-01423-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024]
Abstract
Alcohol-associated liver disease (ALD) is a hepatocyte dysfunction disease caused by chronic or excessive alcohol consumption, which can lead to extensive hepatocyte necrosis and even liver failure. Currently, the pathogenesis of ALD and the anti-ALD mechanisms have not been fully elucidated yet. In this study, we investigated the effects of endoplasmic reticulum autophagy (ER-phagy) in ALD and the role of acid-sensing ion channel 1a (ASIC1a) in ER stress-mediated ER-phagy. A mouse model of ALD was established using the Gao-Binge method and the AML12 cell line treated with alcohol was used as an in vitro model. We showed that ASIC1a expression was significantly increased and ER-phagy was activated in both the in vivo and in vitro models. In alcohol-treated AML12 cells, we showed that blockade of ASIC1a with PcTx-1 or knockdown of ASIC1a reduced alcohol-induced intracellular Ca2+ accumulation and ER stress. In addition, inhibition of ER stress with 4-PBA reduced the level of ER-phagy. Furthermore, knockdown of the ER-phagy receptor family with sequence similarity 134 member B (FAM134B) alleviated alcohol-triggered hepatocyte injury and apoptosis. In conclusion, this study demonstrates that alcohol activates ER stress-induced ER-phagy and liver injury by increasing ASIC1a expression and ASIC1a-mediated Ca2+ influx, providing a novel strategy for the treatment of ALD.
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Affiliation(s)
- Yue-Qin Zhu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
- Office of Clinical Trial Institution, Anhui Provincial Cancer Hospital, Hefei, 230031, China
| | - Li-Li Wang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Zi-Hao Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Shi-Shun Qian
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Zhou Xu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jin Zhang
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Yong-Hu Song
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xue-Sheng Pan
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Na Du
- Department of Pharmacy, Shanghai Songjiang District Central Hospital, Shanghai, 201600, China
| | - Amira Abou-Elnour
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Lynn Jia Tay
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jing-Rong Zhang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Meng-Xue Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yu-Xian Shen
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
| | - Yan Huang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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2
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Farkas E, Rose CR. A dangerous liaison: Spreading depolarization and tissue acidification in cerebral ischemia. J Cereb Blood Flow Metab 2025; 45:201-218. [PMID: 39535276 PMCID: PMC12000947 DOI: 10.1177/0271678x241289756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 08/30/2024] [Accepted: 08/30/2024] [Indexed: 11/16/2024]
Abstract
Brain pH is precisely regulated, and pH transients associated with activity are rapidly restored under physiological conditions. During ischemia, the brain's ability to buffer pH changes is rapidly depleted. Tissue oxygen deprivation causes a shift from aerobic to anaerobic metabolism and the accumulation of lactic acid and protons. Although the degree of tissue acidosis resulting from ischemia depends on the severity of the ischemia, spreading depolarization (SD) events emerge as central elements to determining ischemic tissue acidosis. A marked decrease in tissue pH during cerebral ischemia may exacerbate neuronal injury, which has become known as acidotoxicity, in analogy to excitotoxicity. The cellular pathways underlying acidotoxicity have recently been described in increasing detail. The molecular structure of acid or base carriers and acidosis-activated ion channels, the precise (dys)homeostatic conditions under which they are activated, and their possible role in severe ischemia have been addressed. The expanded understanding of acidotoxic mechanisms now provides an opportunity to reevaluate the contexts that lead to acidotoxic injury. Here, we review the specific cellular pathways of acidotoxicity and demonstrate that SD plays a central role in activating the molecular machinery leading to acid-induced damage. We propose that SD is a key contributor to acidotoxic injury in cerebral ischemia.
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Affiliation(s)
- Eszter Farkas
- Hungarian Centre of Excellence for Molecular Medicine – University of Szeged, Cerebral Blood Flow and Metabolism Research Group, Szeged, Hungary
- Department of Cell Biology and Molecular Medicine, Albert Szent-Györgyi Medical School and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Christine R Rose
- Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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3
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Tuineau MN, Herbert LM, Garcia SM, Resta TC, Jernigan NL. Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2024; 327:L439-L451. [PMID: 39104320 PMCID: PMC11482464 DOI: 10.1152/ajplung.00083.2024] [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: 03/04/2024] [Revised: 07/25/2024] [Accepted: 07/28/2024] [Indexed: 08/07/2024] Open
Abstract
In pulmonary hypertension (PHTN), a metabolic shift to aerobic glycolysis promotes a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs). Enhanced glycolysis induces extracellular acidosis, which can activate proton-sensing membrane receptors and ion channels. We previously reported that activation of the proton-gated cation channel acid-sensing ion channel 1a (ASIC1a) contributes to the development of hypoxic PHTN. Therefore, we hypothesize that enhanced glycolysis and subsequent acidification of the PASMC extracellular microenvironment activate ASIC1a in hypoxic PHTN. We observed decreased oxygen consumption rate and increased extracellular acidification rate in PASMCs from chronic hypoxia (CH)-induced PHTN rats, indicating a shift to aerobic glycolysis. In addition, we found that intracellular alkalization and extracellular acidification occur in PASMCs following CH and in vitro hypoxia, which were prevented by the inhibition of glycolysis with 2-deoxy-d-glucose (2-DG). Inhibiting H+ transport/secretion through carbonic anhydrases, Na+/H+ exchanger 1, or vacuolar-type H+-ATPase did not prevent this pH shift following hypoxia. Although the putative monocarboxylate transporter 1 (MCT1) and -4 (MCT4) inhibitor syrosingopine prevented the pH shift, the specific MCT1 inhibitor AZD3965 and/or the MCT4 inhibitor VB124 were without effect, suggesting that syrosingopine targets the glycolytic pathway independent of H+ export. Furthermore, 2-DG and syrosingopine prevented enhanced ASIC1a-mediated store-operated Ca2+ entry in PASMCs from CH rats. These data suggest that multiple H+ transport mechanisms contribute to extracellular acidosis and that inhibiting glycolysis-rather than specific H+ transporters-more effectively prevents extracellular acidification and ASIC1a activation. Together, these data reveal a novel pathological relationship between glycolysis and ASIC1a activation in hypoxic PHTN.NEW & NOTEWORTHY In pulmonary hypertension, a metabolic shift to aerobic glycolysis drives a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells. We demonstrate that this enhanced glycolysis induces extracellular acidosis and activates the proton-gated ion channel, acid-sensing ion channel 1a (ASIC1a). Although multiple H+ transport/secretion mechanisms are upregulated in PHTN and likely contribute to extracellular acidosis, inhibiting glycolysis with 2-deoxy-d-glucose or syrosingopine effectively prevents extracellular acidification and ASIC1a activation, revealing a promising therapeutic avenue.
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Affiliation(s)
- Megan N Tuineau
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
| | - Lindsay M Herbert
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
| | - Selina M Garcia
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
| | - Thomas C Resta
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
| | - Nikki L Jernigan
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
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4
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Khataei T, Benson CJ. ASIC3 plays a protective role in delayed-onset muscle soreness (DOMS) through muscle acid sensation during exercise. FRONTIERS IN PAIN RESEARCH 2023; 4:1215197. [PMID: 37795390 PMCID: PMC10546048 DOI: 10.3389/fpain.2023.1215197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 08/10/2023] [Indexed: 10/06/2023] Open
Abstract
Immediate exercise-induced pain (IEIP) and DOMS are two types of exercise-induced muscle pain and can act as barriers to exercise. The burning sensation of IEIP occurs during and immediately after intensive exercise, whereas the soreness of DOMS occurs later. Acid-sensing ion channels (ASICs) within muscle afferents are activated by H+ and other chemicals and have been shown to play a role in various chronic muscle pain conditions. Here, we further defined the role of ASICs in IEIP, and also tested if ASIC3 is required for DOMS. After undergoing exhaustive treadmill exercise, exercise-induced muscle pain was assessed in wild-type (WT) and ASIC3-/- mice at baseline via muscle withdrawal threshold (MWT), immediately, and 24 h after exercise. Locomotor movement, grip strength, and repeat exercise performance were tested at baseline and 24 h after exercise to evaluate DOMS. We found that ASIC3-/- had similar baseline muscle pain, locomotor activity, grip strength, and exercise performance as WT mice. WT showed diminished MWT immediately after exercise indicating they developed IEIP, but ASIC3-/- mice did not. At 24 h after baseline exercise, both ASIC3-/- and WT had similarly lower MWT and grip strength, however, ASIC3-/- displayed significantly lower locomotor activity and repeat exercise performance at 24 h time points compared to WT. In addition, ASIC3-/- mice had higher muscle injury as measured by serum lactate dehydrogenase and creatine kinase levels at 24 h after exercise. These results show that ASIC3 is required for IEIP, but not DOMS, and in fact might play a protective role to prevent muscle injury associated with strenuous exercise.
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Affiliation(s)
- Tahsin Khataei
- Department of Internal Medicine, Roy J and Lucile A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
- Iowa City VA Healthcare System, Iowa City, IA, United States
- Department of Health and Human Physiology, University of Iowa, Iowa City, IA, United States
| | - Christopher J. Benson
- Department of Internal Medicine, Roy J and Lucile A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
- Iowa City VA Healthcare System, Iowa City, IA, United States
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5
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Cherninskyi A, Storozhuk M, Maximyuk O, Kulyk V, Krishtal O. Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors. Neurosci Bull 2023; 39:845-862. [PMID: 36445556 PMCID: PMC9707125 DOI: 10.1007/s12264-022-00986-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 08/14/2022] [Indexed: 11/30/2022] Open
Abstract
Adenosine triphosphate (ATP) is well-known as a universal source of energy in living cells. Less known is that this molecule has a variety of important signaling functions: it activates a variety of specific metabotropic (P2Y) and ionotropic (P2X) receptors in neuronal and non-neuronal cell membranes. So, a wide variety of signaling functions well fits the ubiquitous presence of ATP in the tissues. Even more ubiquitous are protons. Apart from the unspecific interaction of protons with any protein, many physiological processes are affected by protons acting on specific ionotropic receptors-acid-sensing ion channels (ASICs). Both protons (acidification) and ATP are locally elevated in various pathological states. Using these fundamentally important molecules as agonists, ASICs and P2X receptors signal a variety of major brain pathologies. Here we briefly outline the physiological roles of ASICs and P2X receptors, focusing on the brain pathologies involving these receptors.
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Affiliation(s)
- Andrii Cherninskyi
- Bogomoletz Institute of Physiology of National Academy of Sciences of Ukraine, Kyiv, 01024, Ukraine.
| | - Maksim Storozhuk
- Bogomoletz Institute of Physiology of National Academy of Sciences of Ukraine, Kyiv, 01024, Ukraine
| | - Oleksandr Maximyuk
- Bogomoletz Institute of Physiology of National Academy of Sciences of Ukraine, Kyiv, 01024, Ukraine
| | - Vyacheslav Kulyk
- Bogomoletz Institute of Physiology of National Academy of Sciences of Ukraine, Kyiv, 01024, Ukraine
| | - Oleg Krishtal
- Bogomoletz Institute of Physiology of National Academy of Sciences of Ukraine, Kyiv, 01024, Ukraine
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6
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Klipp RC, Bankston JR. A loosely coordinated interaction site for arachidonic acid on ASICs. J Gen Physiol 2023; 155:213849. [PMID: 36723670 PMCID: PMC9929933 DOI: 10.1085/jgp.202213307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Molecular dynamics simulations reveal a putative interaction surface for PUFAs on TM1 of ASICs that is not tightly conserved between isoforms.
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Affiliation(s)
- Robert C. Klipp
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - John R. Bankston
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Correspondence to John R. Bankston:
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7
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Ananchenko A, Musgaard M. Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains. J Gen Physiol 2023; 155:213797. [PMID: 36625864 PMCID: PMC9836442 DOI: 10.1085/jgp.202213259] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/20/2022] [Accepted: 12/21/2022] [Indexed: 01/11/2023] Open
Abstract
Acid-sensing ion channels (ASICs) play important roles in inflammatory pathways by conducting ions across the neuronal membrane in response to proton binding under acidic conditions. Recent studies have shown that ASICs can be modulated by arachidonic acid (AA), and, in the case of the ASIC3 subtype, even activated by AA at physiological pH. However, the mechanism by which these fatty acids act on the channel is still unknown. Here, we have used multiscale molecular dynamics simulations to predict a putative, general binding region of AA to models of the human ASIC protein. We have identified, in agreement with recent studies, residues in the outer leaflet transmembrane region which interact with AA. In addition, despite their similar modulation, we observe subtle differences in the AA interaction pattern between human ASIC1a and human ASIC3, which can be reversed by mutating three key residues at the outer leaflet portion of TM1. We further probed interactions with these residues in hASIC3 using atomistic simulations and identified possible AA coordinating interactions; salt bridge interactions of AA with R65hASIC3 and R68hASIC3 and AA tail interactions with the Y58hASIC3 aromatic ring. We have shown that longer fatty acid tails with more double bonds have increased relative occupancy in this region of the channel, a finding supported by recent functional studies. We further proposed that the modulatory effect of AA on ASIC does not result from changes in local membrane curvature. Rather, we speculate that it may occur through structural changes to the ion channel upon AA binding.
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Affiliation(s)
- Anna Ananchenko
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
| | - Maria Musgaard
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada
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8
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Liin SI. ASIC3, a proton-gated ion channel with preference for polyunsaturated lipids with specific headgroup and tail properties. J Gen Physiol 2022; 154:e202213171. [PMID: 35583814 PMCID: PMC9121178 DOI: 10.1085/jgp.202213171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Commentary highlighting valuable mechanistic insights provided by Klipp and Bankston on ASIC3 regulation by lipids.
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Affiliation(s)
- Sara I. Liin
- Department of Biomedical and Clinical Sciences, Division of Neurobiology, Linköping University, Linköping, Sweden
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9
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Klipp RC, Bankston JR. Structural determinants of acid-sensing ion channel potentiation by single chain lipids. J Gen Physiol 2022; 154:e202213156. [PMID: 35583813 PMCID: PMC9120901 DOI: 10.1085/jgp.202213156] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/02/2022] [Indexed: 01/07/2023] Open
Abstract
Acid-sensing ion channels (ASICs) are sensitized to activation by inflammatory mediators such as the polyunsaturated fatty acid (PUFA) arachidonic acid (AA). Previous work has shown that AA can potentiate ASIC currents at subsaturating proton concentrations, but the structural mechanisms of this change in gating are not understood. Here we show that PUFAs cause multiple gating changes in ASIC3, including shifting the pH dependence of activation, slowing the rate of desensitization, and increasing the current even at a saturating pH. The impact on gating depends on the nature of both the head and tail of the lipid, with the head group structure primarily determining the magnitude of the effect on the channel. An N-acyl amino acid (NAAA), arachidonyl glycine (AG), is such a strong regulator that it can act as a ligand at neutral pH. Mutation of an arginine in the outer segment of TM1 (R64) eliminated the effect of docosahexaenoic acid (DHA) even at high concentrations, suggesting a potential interaction site for the lipid on the channel. Our results suggest a model in which PUFAs bind to ASICs via both their tail group and an electrostatic interaction between the negatively charged PUFA head group and the positively charged arginine side chain. These data provide the first look at the structural features of lipids that are important for modulating ASICs and suggest a potential binding site for PUFAs on the channel.
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Affiliation(s)
- Robert C. Klipp
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - John R. Bankston
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO
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10
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Foster VS, Rash LD, King GF, Rank MM. Acid-Sensing Ion Channels: Expression and Function in Resident and Infiltrating Immune Cells in the Central Nervous System. Front Cell Neurosci 2021; 15:738043. [PMID: 34602982 PMCID: PMC8484650 DOI: 10.3389/fncel.2021.738043] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/30/2021] [Indexed: 11/15/2022] Open
Abstract
Peripheral and central immune cells are critical for fighting disease, but they can also play a pivotal role in the onset and/or progression of a variety of neurological conditions that affect the central nervous system (CNS). Tissue acidosis is often present in CNS pathologies such as multiple sclerosis, epileptic seizures, and depression, and local pH is also reduced during periods of ischemia following stroke, traumatic brain injury, and spinal cord injury. These pathological increases in extracellular acidity can activate a class of proton-gated channels known as acid-sensing ion channels (ASICs). ASICs have been primarily studied due to their ubiquitous expression throughout the nervous system, but it is less well recognized that they are also found in various types of immune cells. In this review, we explore what is currently known about the expression of ASICs in both peripheral and CNS-resident immune cells, and how channel activation during pathological tissue acidosis may lead to altered immune cell function that in turn modulates inflammatory pathology in the CNS. We identify gaps in the literature where ASICs and immune cell function has not been characterized, such as neurotrauma. Knowledge of the contribution of ASICs to immune cell function in neuropathology will be critical for determining whether the therapeutic benefits of ASIC inhibition might be due in part to an effect on immune cells.
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Affiliation(s)
- Victoria S. Foster
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Lachlan D. Rash
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Glenn F. King
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, St Lucia, QLD, Australia
| | - Michelle M. Rank
- Anatomy and Physiology, Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
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11
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Redd MA, Scheuer SE, Saez NJ, Yoshikawa Y, Chiu HS, Gao L, Hicks M, Villanueva JE, Joshi Y, Chow CY, Cuellar-Partida G, Peart JN, See Hoe LE, Chen X, Sun Y, Suen JY, Hatch RJ, Rollo B, Xia D, Alzubaidi MAH, Maljevic S, Quaife-Ryan GA, Hudson JE, Porrello ER, White MY, Cordwell SJ, Fraser JF, Petrou S, Reichelt ME, Thomas WG, King GF, Macdonald PS, Palpant NJ. Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation 2021; 144:947-960. [PMID: 34264749 DOI: 10.1161/circulationaha.121.054360] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0-6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods: We used genetic and pharmacological methods to investigate the role of acid sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole organ level. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Results: Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction (MI) and two models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.
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Affiliation(s)
- Meredith A Redd
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
- Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia (M.A.R., L.E.S.H., J.Y.S., J.F.F.)
| | - Sarah E Scheuer
- Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.)
- Cardiopulmonary Transplant Unit (S.E.S., Y.J., P.S.M.), St Vincent's Hospital, Sydney, Australia
- Faculty of Medicine, University of New South Wales, Sydney, Australia (S.E.S., M.H., J.E.V., Y.J., P.S.M.)
| | - Natalie J Saez
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science (N.J.S., G.F.K.), The University of Queensland, St Lucia, Australia
| | - Yusuke Yoshikawa
- School of Biomedical Sciences (Y.Y., M.E.R., W.G.T.), The University of Queensland, St Lucia, Australia
| | - Han Sheng Chiu
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
| | - Ling Gao
- Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.)
| | - Mark Hicks
- Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.)
- Department of Pharmacology (M.H.), St Vincent's Hospital, Sydney, Australia
- Faculty of Medicine, University of New South Wales, Sydney, Australia (S.E.S., M.H., J.E.V., Y.J., P.S.M.)
| | - Jeanette E Villanueva
- Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.)
- Faculty of Medicine, University of New South Wales, Sydney, Australia (S.E.S., M.H., J.E.V., Y.J., P.S.M.)
| | - Yashutosh Joshi
- Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.)
- Cardiopulmonary Transplant Unit (S.E.S., Y.J., P.S.M.), St Vincent's Hospital, Sydney, Australia
- Faculty of Medicine, University of New South Wales, Sydney, Australia (S.E.S., M.H., J.E.V., Y.J., P.S.M.)
| | - Chun Yuen Chow
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
| | - Gabriel Cuellar-Partida
- The University of Queensland Diamantina Institute, Faculty of Medicine and Translational Research Institute, Woolloongabba, Australia (G.C.-P.)
| | - Jason N Peart
- School of Medical Science, Griffith University, Southport, Australia (J.N.P.)
| | - Louise E See Hoe
- Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia (M.A.R., L.E.S.H., J.Y.S., J.F.F.)
- Faculty of Medicine, The University of Queensland, Brisbane, Australia (L.E.S.H., J.Y.S., J.F.F.)
| | - Xiaoli Chen
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
| | - Yuliangzi Sun
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia (M.A.R., L.E.S.H., J.Y.S., J.F.F.)
- Faculty of Medicine, The University of Queensland, Brisbane, Australia (L.E.S.H., J.Y.S., J.F.F.)
| | - Robert J Hatch
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia (R.J.H., B.R., S.M., S.P.)
| | - Ben Rollo
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia (R.J.H., B.R., S.M., S.P.)
| | - Di Xia
- Genome Innovation Hub (D.X.), The University of Queensland, St Lucia, Australia
| | - Mubarak A H Alzubaidi
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
| | - Snezana Maljevic
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia (R.J.H., B.R., S.M., S.P.)
| | | | - James E Hudson
- QIMR Berghofer Medical Research Institute, Brisbane, Australia (G.A.Q.-R., J.E.H.)
| | - Enzo R Porrello
- Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia (E.R.P.)
- Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, Australia (E.R.P.)
| | - Melanie Y White
- School of Medical Sciences, School of Life and Environmental Sciences, and Charles Perkins Centre, The University of Sydney, Sydney, Australia (M.Y.W., S.J.C.)
| | - Stuart J Cordwell
- School of Medical Sciences, School of Life and Environmental Sciences, and Charles Perkins Centre, The University of Sydney, Sydney, Australia (M.Y.W., S.J.C.)
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia (M.A.R., L.E.S.H., J.Y.S., J.F.F.)
- Faculty of Medicine, The University of Queensland, Brisbane, Australia (L.E.S.H., J.Y.S., J.F.F.)
| | - Steven Petrou
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia (R.J.H., B.R., S.M., S.P.)
| | - Melissa E Reichelt
- School of Biomedical Sciences (Y.Y., M.E.R., W.G.T.), The University of Queensland, St Lucia, Australia
| | - Walter G Thomas
- School of Biomedical Sciences (Y.Y., M.E.R., W.G.T.), The University of Queensland, St Lucia, Australia
| | - Glenn F King
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science (N.J.S., G.F.K.), The University of Queensland, St Lucia, Australia
| | - Peter S Macdonald
- Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.)
- Cardiopulmonary Transplant Unit (S.E.S., Y.J., P.S.M.), St Vincent's Hospital, Sydney, Australia
- Faculty of Medicine, University of New South Wales, Sydney, Australia (S.E.S., M.H., J.E.V., Y.J., P.S.M.)
| | - Nathan J Palpant
- Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia
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12
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Choi DW. Excitotoxicity: Still Hammering the Ischemic Brain in 2020. Front Neurosci 2020; 14:579953. [PMID: 33192266 PMCID: PMC7649323 DOI: 10.3389/fnins.2020.579953] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/25/2020] [Indexed: 12/13/2022] Open
Abstract
Interest in excitotoxicity expanded following its implication in the pathogenesis of ischemic brain injury in the 1980s, but waned subsequent to the failure of N-methyl-D-aspartate (NMDA) antagonists in high profile clinical stroke trials. Nonetheless there has been steady progress in elucidating underlying mechanisms. This review will outline the historical path to current understandings of excitotoxicity in the ischemic brain, and suggest that this knowledge should be leveraged now to develop neuroprotective treatments for stroke.
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Affiliation(s)
- Dennis W Choi
- Department of Neurology, SUNY Stony Brook, Stony Brook, NY, United States
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13
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Osmakov DI, Khasanov TA, Andreev YA, Lyukmanova EN, Kozlov SA. Animal, Herb, and Microbial Toxins for Structural and Pharmacological Study of Acid-Sensing Ion Channels. Front Pharmacol 2020; 11:991. [PMID: 32733241 PMCID: PMC7360831 DOI: 10.3389/fphar.2020.00991] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/19/2020] [Indexed: 12/22/2022] Open
Abstract
Acid-sensing ion channels (ASICs) are of the most sensitive molecular sensors of extracellular pH change in mammals. Six isoforms of these channels are widely represented in membranes of neuronal and non-neuronal cells, where these molecules are involved in different important regulatory functions, such as synaptic plasticity, learning, memory, and nociception, as well as in various pathological states. Structural and functional studies of both wild-type and mutant ASICs are essential for human care and medicine for the efficient treatment of socially significant diseases and ensure a comfortable standard of life. Ligands of ASICs serve as indispensable tools for these studies. Such bioactive compounds can be synthesized artificially. However, to date, the search for such molecules has been most effective amongst natural sources, such as animal venoms or plants and microbial extracts. In this review, we provide a detailed and comprehensive structural and functional description of natural compounds acting on ASICs, as well as the latest information on structural aspects of their interaction with the channels. Many of the examples provided in the review demonstrate the undoubted fundamental and practical successes of using natural toxins. Without toxins, it would not be possible to obtain data on the mechanisms of ASICs' functioning, provide detailed study of their pharmacological properties, or assess the contribution of the channels to development of different pathologies. The selectivity to different isoforms and variety in the channel modulation mode allow for the appraisal of prospective candidates for the development of new drugs.
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Affiliation(s)
- Dmitry I Osmakov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Timur A Khasanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia
| | - Yaroslav A Andreev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ekaterina N Lyukmanova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia
| | - Sergey A Kozlov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia
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14
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Khataei T, Harding AMS, Janahmadi M, El-Geneidy M, Agha-Alinejad H, Rajabi H, Snyder PM, Sluka KA, Benson CJ. ASICs are required for immediate exercise-induced muscle pain and are downregulated in sensory neurons by exercise training. J Appl Physiol (1985) 2020; 129:17-26. [PMID: 32463731 DOI: 10.1152/japplphysiol.00033.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Exercise training is an effective therapy for many pain-related conditions, and trained athletes have lower pain perception compared with unconditioned people. Some painful conditions, including strenuous exercise, are associated with elevated levels of protons, metabolites, and inflammatory factors, which may activate receptors and/or ion channels, including acid-sensing ion channels (ASICs), on nociceptive sensory neurons. We hypothesized that ASICs are required for immediate exercise-induced muscle pain (IEIP) and that exercise training diminishes IEIP by modulating ASICs within muscle afferents. We found high-intensity interval training (HIIT) reduced IEIP in C57BL/6 mice and diminished ASIC mRNA levels in lumber dorsal root ganglia, and this downregulation of ASICs correlated with improved exercise capacity. Additionally, we found that ASIC3 -/- mice did not develop IEIP; however, the exercise capacity of ASIC3 -/- was similar to wild-type mice. These results suggest that ASICs are required for IEIP and that diminishment of IEIP after exercise training correlates with downregulation of ASICs in sensory neurons.NEW & NOTEWORTHY Exercise performance can be limited by the sensations of muscle fatigue and pain transmitted by muscle afferents. It has been proposed that exercise training abrogates these negative feedback signals. We found that acid-sensing ion channels (ASICs) are required for immediate exercise-induced muscle pain (IEIP). Moreover, exercise training prevented IEIP and was correlated with downregulation of ASICs in sensory neurons.
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Affiliation(s)
- Tahsin Khataei
- Department of Exercise Physiology, Tarbiat Modares University, Tehran, Iran.,Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | - Anne Marie S Harding
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | - Mahyar Janahmadi
- Department of Physiology and Neuroscience Research Center, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maram El-Geneidy
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | | | - Hamid Rajabi
- Department of Exercise Physiology, Kharazmi University, Tehran, Iran
| | - Peter M Snyder
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | - Kathleen A Sluka
- Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, Iowa.,Neuroscience Institute, The University of Iowa, Iowa City, Iowa
| | - Christopher J Benson
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa.,Department of Pharmacology, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa
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15
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A molecular view of the function and pharmacology of acid-sensing ion channels. Pharmacol Res 2020; 154:104166. [DOI: 10.1016/j.phrs.2019.02.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/01/2019] [Accepted: 02/02/2019] [Indexed: 02/06/2023]
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16
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Lai K, Song XL, Shi HS, Qi X, Li CY, Fang J, Wang F, Maximyuk O, Krishtal O, Xu TL, Li XY, Ni K, Li WP, Shi HB, Wang LY, Yin SK. Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice. Sci Transl Med 2020; 12:12/530/eaax1337. [PMID: 32051225 DOI: 10.1126/scitranslmed.aax1337] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 08/03/2019] [Accepted: 12/10/2019] [Indexed: 12/24/2022]
Abstract
Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.
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Affiliation(s)
- Ke Lai
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
| | - Xing-Lei Song
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hao-Song Shi
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
| | - Xin Qi
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chun-Yan Li
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
| | - Jia Fang
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
| | - Fan Wang
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
| | | | - Oleg Krishtal
- Bogomoletz Institute of Physiology of NAS Ukraine, Kyiv 01024, Ukraine
| | - Tian-Le Xu
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiao-Yan Li
- Department of Otorhinolaryngology, Shanghai Children Hospital and Shanghai Jiao Tong University, Shanghai 200062, China
| | - Kun Ni
- Department of Otorhinolaryngology, Shanghai Children Hospital and Shanghai Jiao Tong University, Shanghai 200062, China
| | - Wan-Peng Li
- Department of Otorhinolaryngology, Shanghai Children Hospital and Shanghai Jiao Tong University, Shanghai 200062, China
| | - Hai-Bo Shi
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
| | - Lu-Yang Wang
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto M5G 1X8, Canada
- Department of Physiology, University of Toronto, Toronto M5S 1A1, Canada
| | - Shan-Kai Yin
- Department of Otorhinolaryngology, Sixth People’s Hospital of Shanghai and Shanghai Jiao Tong University, Shanghai 200032, China
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17
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Pattison LA, Callejo G, St John Smith E. Evolution of acid nociception: ion channels and receptors for detecting acid. Philos Trans R Soc Lond B Biol Sci 2019; 374:20190291. [PMID: 31544616 PMCID: PMC6790391 DOI: 10.1098/rstb.2019.0291] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2019] [Indexed: 12/13/2022] Open
Abstract
Nociceptors, i.e. sensory neurons tuned to detect noxious stimuli, are found in numerous phyla of the Animalia kingdom and are often polymodal, responding to a variety of stimuli, e.g. heat, cold, pressure and chemicals, such as acid. Owing to the ability of protons to have a profound effect on ionic homeostasis and damage macromolecular structures, it is no wonder that the ability to detect acid is conserved across many species. To detect changes in pH, nociceptors are equipped with an assortment of different acid sensors, some of which can detect mild changes in pH, such as the acid-sensing ion channels, proton-sensing G protein-coupled receptors and several two-pore potassium channels, whereas others, such as the transient receptor potential vanilloid 1 ion channel, require larger shifts in pH. This review will discuss the evolution of acid sensation and the different mechanisms by which nociceptors can detect acid. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
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Affiliation(s)
| | | | - Ewan St John Smith
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
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18
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Uchitel OD, González Inchauspe C, Weissmann C. Synaptic signals mediated by protons and acid-sensing ion channels. Synapse 2019; 73:e22120. [PMID: 31180161 DOI: 10.1002/syn.22120] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 01/04/2023]
Abstract
Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca2+ currents through multivesicular release in ribbon-type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid-sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca2+ through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine-seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.
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Affiliation(s)
- Osvaldo D Uchitel
- Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado", Facultad de Ciencias Exactas y Naturales, Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) CONICET, Universidad de Buenos Aires, Ciudad Universitaria, (C1428EGA), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlota González Inchauspe
- Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado", Facultad de Ciencias Exactas y Naturales, Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) CONICET, Universidad de Buenos Aires, Ciudad Universitaria, (C1428EGA), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carina Weissmann
- Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado", Facultad de Ciencias Exactas y Naturales, Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) CONICET, Universidad de Buenos Aires, Ciudad Universitaria, (C1428EGA), Ciudad Autónoma de Buenos Aires, Argentina
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19
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González-Inchauspe C, Gobetto MN, Uchitel OD. Modulation of acid sensing ion channel dependent protonergic neurotransmission at the mouse calyx of Held. Neuroscience 2019; 439:195-210. [PMID: 31022462 DOI: 10.1016/j.neuroscience.2019.04.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 11/18/2022]
Abstract
Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. It has been reported that homomeric ASIC-1a channels are expressed in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H+ from synaptic vesicles activates postsynaptic ASIC-1a channels in mice up to 3 weeks old. This generates synaptic currents (ASIC1a-SCs) that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that neuromodulators like histamine and natural products like lactate and spermine potentiate ASIC1a-SCs in an additive form such that excitatory ASIC synaptic currents as well as the associated calcium influx become significantly large and physiologically relevant. We show that ASIC1a-SCs enhanced by endogenous neuromodulators are capable of supporting synaptic transmission in the absence of glutamatergic EPSCs. Furthermore, at high frequency stimulation (HFS), ASIC1a-SCs contribute to diminish short term depression (STD) and their contribution is even more relevant at early stages of development. Since ASIC channels are present in almost all types of neurons and synaptic vesicles content is acid, the participation of protons in synaptic transmission and its potentiation by endogenous substances could be a general phenomenon across the central nervous system. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Affiliation(s)
- Carlota González-Inchauspe
- Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) CONICET. Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado", Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Ciudad Universitaria. (C1428EGA) Ciudad Autónoma de Buenos Aires, Argentina.
| | - María Natalia Gobetto
- Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) CONICET. Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado", Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Ciudad Universitaria. (C1428EGA) Ciudad Autónoma de Buenos Aires, Argentina
| | - Osvaldo D Uchitel
- Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) CONICET. Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado", Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Ciudad Universitaria. (C1428EGA) Ciudad Autónoma de Buenos Aires, Argentina
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20
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Roles of volume-regulatory anion channels, VSOR and Maxi-Cl, in apoptosis, cisplatin resistance, necrosis, ischemic cell death, stroke and myocardial infarction. CURRENT TOPICS IN MEMBRANES 2019; 83:205-283. [PMID: 31196606 DOI: 10.1016/bs.ctm.2019.03.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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21
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Shteinikov VY, Barygin OI, Gmiro VE, Tikhonov DB. Multiple modes of action of hydrophobic amines and their guanidine analogues on ASIC1a. Eur J Pharmacol 2018; 844:183-194. [PMID: 30557561 DOI: 10.1016/j.ejphar.2018.12.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/11/2018] [Accepted: 12/12/2018] [Indexed: 01/22/2023]
Abstract
Hydrophobic monoamines containing only a hydrophobic/aromatic moiety and protonated amino group are a recently described class of acid-sensing ion channel (ASIC) modulators. Intensive studies have revealed a number of active compounds including endogenous amines and pharmacological agents and shown that these compounds potentiate and inhibit ASICs depending on their specific structure and on subunit composition of the target channel. The action of monoamines also depends on the application protocol, membrane voltage, conditioning and activating pH, suggesting complex mechanism(s) of the ligand-receptor interaction. Without understanding of these mechanisms analysis of structure-function relationships and predictive search for new potent and selective drugs are hardly possible. To this end, we investigated the modes of action for a representative series of amine and guanidine derivatives of adamantane and phenylcyclohexyl. The study was performed on transfected Chinese hamster ovary (CHO) cells and rat hippocampal interneurons using whole-cell patch clamp recording. We found that complex picture of monoamine action can be rationalized assuming four modes of action: (1) voltage-dependent pore block, (2) acidic shift of activation, (3) alkaline shift of activation and (4) acidic shift of steady-state desensitization. Structure-activity relationships are discussed in the light of this framework. The experiments on native heteromeric ASICs have shown that some of these mechanisms are shared between them and recombinant ASIC1a, implying that our results could also be relevant for amine action in physiological and pathological conditions.
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Affiliation(s)
- Vasilii Y Shteinikov
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg 194223, Russia.
| | - Oleg I Barygin
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg 194223, Russia
| | - Valery E Gmiro
- Institute of Experimental Medicine, RAMS, St. Petersburg 197376, Russia
| | - Denis B Tikhonov
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg 194223, Russia
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22
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do Nascimento JET, de Morais SM, de Lisboa DS, de Oliveira Sousa M, Santos SAAR, Magalhães FEA, Campos AR. The orofacial antinociceptive effect of Kaempferol-3-O-rutinoside, isolated from the plant Ouratea fieldingiana, on adult zebrafish (Danio rerio). Biomed Pharmacother 2018; 107:1030-1036. [PMID: 30257314 DOI: 10.1016/j.biopha.2018.08.089] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 08/04/2018] [Accepted: 08/15/2018] [Indexed: 01/29/2023] Open
Abstract
The aim of this study was to evaluate the antinociceptive effect of Kaempferol-3-O-rutinoside (KR), isolated from the plant Ouratea fieldingiana, on the orofacial nociception and possible mechanisms of action. Adult zebrafish (Danio rerio) were tested as a behavioral model to study formalin, glutamate, capsaicin, cinnamaldehyde and acidic saline-induced orofacial nociception, using as parameter the number of times the fish crossed the lines between the quadrants of a glass Petri dish during a specific time. Morphine was used as positive control. The effect of KR was tested for modulation by opioid (naloxone), nitrergic (L-NAME), TRPV1 (ruthenium red), TRPA1 (camphor) or ASIC (amiloride) antagonists. The effect of KR on zebrafish locomotor behavior was evaluated with the open field test. KR did not alter the fish's locomotor system and significantly reduced the orofacial nociceptive behavior induced by all noxious agents compared to the control group. The antinociceptive effect of KR was similar to morphine. All antagonists inhibited the antinociceptive effect of KR. KR has pharmacological potential for the treatment of acute orofacial pain and this effect is modulated by the opioid and nitrergic systems as well as TRPV1, TRPA1 and ASIC channels. These results can lead to the development of a new natural product for the treatment of orofacial pain and confirm the popular use of O. fieldingiana leaf for pain relief.
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Affiliation(s)
- José Eranildo Teles do Nascimento
- Programa de Pós-Graduação em Ciências Veterinárias, Núcleo de Pesquisa em Sanidade Animal, Universidade Estadual do Ceará, Brazil; Laboratório de Química de Produtos Naturais (LQPN), Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil; Instituto Federal do Ceará, Campus Itapipoca, Ceará, Brazil
| | - Selene Maia de Morais
- Programa de Pós-Graduação em Ciências Veterinárias, Núcleo de Pesquisa em Sanidade Animal, Universidade Estadual do Ceará, Brazil; Laboratório de Química de Produtos Naturais (LQPN), Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil.
| | - Daniele Silva de Lisboa
- Laboratório de Química de Produtos Naturais (LQPN), Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Matheus de Oliveira Sousa
- Laboratório de Química de Produtos Naturais (LQPN), Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Sacha Aubrey Alves Rodrigues Santos
- Núcleo de Biologia Experimental, Universidade de Fortaleza, Fortaleza, Ceará, Brazil; Laboratório de Bioprospecção de Produtos Naturais e Biotecnologia (LBPNB), Universidade Estadual do Ceará (UECE), Tauá, Ceará, Brazil
| | - Francisco Ernani Alves Magalhães
- Núcleo de Biologia Experimental, Universidade de Fortaleza, Fortaleza, Ceará, Brazil; Laboratório de Bioprospecção de Produtos Naturais e Biotecnologia (LBPNB), Universidade Estadual do Ceará (UECE), Tauá, Ceará, Brazil
| | - Adriana Rolim Campos
- Núcleo de Biologia Experimental, Universidade de Fortaleza, Fortaleza, Ceará, Brazil
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Husson Z, Smith ESJ. Naked mole-rat cortical neurons are resistant to acid-induced cell death. Mol Brain 2018; 11:26. [PMID: 29739425 PMCID: PMC5941639 DOI: 10.1186/s13041-018-0369-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/27/2018] [Indexed: 01/02/2023] Open
Abstract
Regulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na+ permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs, Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Here, we show with whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons that NMR neurons have smaller voltage-gated Na+ channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are reversibly blocked by the ASIC antagonist benzamil. We further demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. In summary, NMR neurons show significant cellular resistance to acidotoxicity compared to mouse neurons, contributing factors likely to be smaller ASIC-mediated currents and reduced NaV activity.
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Affiliation(s)
- Zoé Husson
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
| | - Ewan St John Smith
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
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24
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Shteinikov VY, Tikhonova TB, Korkosh VS, Tikhonov DB. Potentiation and Block of ASIC1a by Memantine. Cell Mol Neurobiol 2018; 38:869-881. [PMID: 29058095 PMCID: PMC11481973 DOI: 10.1007/s10571-017-0561-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 10/17/2017] [Indexed: 01/02/2023]
Abstract
Acid-sensing ion channels (ASICs) are modulated by various classes of ligands, including the recently described hydrophobic monoamines, which inhibit and potentiate ASICs in a subunit-specific manner. In particular, memantine inhibits ASIC1a and potentiates ASIC2a homomers. The aim of the present work was to characterize action mechanism of memantine on recombinant ASIC1a expressed in CHO (Chinese hamster ovary) cells. We have demonstrated that effect of memantine on ASIC1a strongly depends on membrane voltage, conditioning pH value and application protocol. When applied simultaneously with activating acidification at hyperpolarized voltages, memantine caused the strongest inhibition. Surprisingly, application of memantine between ASIC1a activations at zero voltage caused significant potentiation. Analysis of the data suggests that memantine produces two separate effects, voltage-dependent open-channel block and shift of steady-state desensitization curve to more acidic values. Putative binding sites are discussed based on the computer docking of memantine to the acidic pocket and the pore region.
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Affiliation(s)
- Vasiliy Y Shteinikov
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St.Petersburg, Russia
| | - Tatiana B Tikhonova
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St.Petersburg, Russia
| | - Vyacheslav S Korkosh
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St.Petersburg, Russia
| | - Denis B Tikhonov
- I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St.Petersburg, Russia.
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25
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Rahmati N, Hoebeek FE, Peter S, De Zeeuw CI. Chloride Homeostasis in Neurons With Special Emphasis on the Olivocerebellar System: Differential Roles for Transporters and Channels. Front Cell Neurosci 2018; 12:101. [PMID: 29765304 PMCID: PMC5938380 DOI: 10.3389/fncel.2018.00101] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 03/28/2018] [Indexed: 12/14/2022] Open
Abstract
The intraneuronal ionic composition is an important determinant of brain functioning. There is growing evidence that aberrant homeostasis of the intracellular concentration of Cl- ([Cl-]i) evokes, in addition to that of Na+ and Ca2+, robust impairments of neuronal excitability and neurotransmission and thereby neurological conditions. More specifically, understanding the mechanisms underlying regulation of [Cl-]i is crucial for deciphering the variability in GABAergic and glycinergic signaling of neurons, in both health and disease. The homeostatic level of [Cl-]i is determined by various regulatory mechanisms, including those mediated by plasma membrane Cl- channels and transporters. This review focuses on the latest advances in identification, regulation and characterization of Cl- channels and transporters that modulate neuronal excitability and cell volume. By putting special emphasis on neurons of the olivocerebellar system, we establish that Cl- channels and transporters play an indispensable role in determining their [Cl-]i and thereby their function in sensorimotor coordination.
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Affiliation(s)
- Negah Rahmati
- Department of Neuroscience, Erasmus Medical Center, Rotterdam, Netherlands
| | - Freek E. Hoebeek
- Department of Neuroscience, Erasmus Medical Center, Rotterdam, Netherlands
- NIDOD Institute, Wilhelmina Children's Hospital, University Medical Center Utrecht and Brain Center Rudolf Magnus, Utrecht, Netherlands
| | - Saša Peter
- Department of Neuroscience, Erasmus Medical Center, Rotterdam, Netherlands
| | - Chris I. De Zeeuw
- Department of Neuroscience, Erasmus Medical Center, Rotterdam, Netherlands
- Netherlands Institute for Neuroscience, Royal Dutch Academy for Arts and Sciences, Amsterdam, Netherlands
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26
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Barygin OI, Komarova MS, Tikhonova TB, Korosteleva AS, Nikolaev MV, Magazanik LG, Tikhonov DB. Complex action of tyramine, tryptamine and histamine on native and recombinant ASICs. Channels (Austin) 2017; 11:648-659. [PMID: 29130788 DOI: 10.1080/19336950.2017.1394557] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Proton-gated channels of the ASIC family are widely distributed in the mammalian brain, and, according to the recent data, participate in synaptic transmission. However, ASIC-mediated currents are small, and special efforts are required to detect them. This prompts the search for endogenous ASIC ligands, which can activate or potentiate these channels. A recent finding of the potentiating action of histamine on recombinant homomeric ASIC1a has directed attention to amine-containing compounds. In the present study, we have analyzed the action of histamine, tyramine, and tryptamine on native and recombinant ASICs. None of the compounds caused potentiation of native ASICs in hippocampal interneurons. Furthermore, when applied simultaneously with channel activation, they produced voltage-dependent inhibition. Experiments on recombinant ASIC1a and ASIC2a allowed for an interpretation of these findings. Histamine and tyramine were found to be inactive on the ASIC2a, while tryptamine demonstrated weak inhibition. However, they induce both voltage-dependent inhibition of open channels and voltage-independent potentiation of closed/desensitized channels on the ASIC1a. We suggest that the presence of an ASIC2a subunit in heteromeric native ASICs prevents potentiation but not inhibition. As a result, the inhibitory action of histamine, which is masked by a strong potentiating effect on the ASIC1a homomers, becomes pronounced in experiments with native ASICs.
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Affiliation(s)
- Oleg I Barygin
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
| | - Margarita S Komarova
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
| | - Tatyana B Tikhonova
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
| | - Anastasiia S Korosteleva
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
| | - Maxim V Nikolaev
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
| | - Lev G Magazanik
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
| | - Denis B Tikhonov
- a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry , Russian Academy of Sciences , Saint-Petersburg , Russia
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27
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Ievglevskyi O, Isaev D, Netsyk O, Romanov A, Fedoriuk M, Maximyuk O, Isaeva E, Akaike N, Krishtal O. Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy. Philos Trans R Soc Lond B Biol Sci 2017; 371:rstb.2015.0431. [PMID: 27377725 DOI: 10.1098/rstb.2015.0431] [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] [Accepted: 04/18/2016] [Indexed: 12/12/2022] Open
Abstract
Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca(2+)-permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg(2+) model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo Our results reveal a significant novel role for ASICs.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
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Affiliation(s)
- O Ievglevskyi
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - D Isaev
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - O Netsyk
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - A Romanov
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - M Fedoriuk
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - O Maximyuk
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - E Isaeva
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
| | - N Akaike
- Research Division for Clinical Pharmacology, Medical Corporation, JyuryoGroup, Kumamoto Kinoh Hospital, 6-8-1 Yamamuro, Kitaku, Kumamoto 860-8518, Japan
| | - O Krishtal
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine
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28
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Acid-Sensing Ion Channels as Potential Therapeutic Targets in Neurodegeneration and Neuroinflammation. Mediators Inflamm 2017; 2017:3728096. [PMID: 29056828 PMCID: PMC5625748 DOI: 10.1155/2017/3728096] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Revised: 07/29/2017] [Accepted: 08/13/2017] [Indexed: 12/21/2022] Open
Abstract
Acid-sensing ion channels (ASICs) are a family of proton-sensing channels that are voltage insensitive, cation selective (mostly permeable to Na+), and nonspecifically blocked by amiloride. Derived from 5 genes (ACCN1-5), 7 subunits have been identified, 1a, 1b, 2a, 2b, 3, 4, and 5, that are widely expressed in the peripheral and central nervous system as well as other tissues. Over the years, different studies have shown that activation of these channels is linked to various physiological and pathological processes, such as memory, learning, fear, anxiety, ischemia, and multiple sclerosis to name a few, so their potential as therapeutic targets is increasing. This review focuses on recent advances that have helped us to better understand the role played by ASICs in different pathologies related to neurodegenerative diseases, inflammatory processes, and pain.
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29
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Osmakov DI, Koshelev SG, Andreev YA, Kozlov SA. Endogenous Isoquinoline Alkaloids Agonists of Acid-Sensing Ion Channel Type 3. Front Mol Neurosci 2017; 10:282. [PMID: 28955199 PMCID: PMC5602355 DOI: 10.3389/fnmol.2017.00282] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/21/2017] [Indexed: 12/21/2022] Open
Abstract
Acid-sensing ion channels (ASICs) ASIC3 expressed mainly in peripheral sensory neurons play an important role in pain perception and inflammation development. In response to acidic stimuli, they can generate a unique biphasic current. At physiological pH 7.4, human ASIC3 isoform (hASIC3) is desensitized and able to generate only a sustained current. We found endogenous isoquinoline alkaloids (EIAs), which restore hASIC3 from desensitization and recover the transient component of the current. Similarly, rat ASIC3 isoform (rASIC3) can also be restored from desensitization (at pH < 7.0) by EIAs with the same potency. At physiological pH and above, EIAs at high concentrations were able to effectively activate hASIC3 and rASIC3. Thus, we found first endogenous agonists of ASIC3 channels that could both activate and prevent or reverse desensitization of the channel. The decrease of EIA levels could be suggested as a novel therapeutic strategy for treatment of pain and inflammation.
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Affiliation(s)
- Dmitry I Osmakov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesMoscow, Russia.,Institute of Molecular Medicine, Sechenov First Moscow State Medical UniversityMoscow, Russia
| | - Sergey G Koshelev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesMoscow, Russia
| | - Yaroslav A Andreev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesMoscow, Russia.,Institute of Molecular Medicine, Sechenov First Moscow State Medical UniversityMoscow, Russia
| | - Sergey A Kozlov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesMoscow, Russia
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30
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Hoshikawa M, Kato A, Hojo H, Shibata Y, Kumamoto N, Watanabe M, Ugawa S. Distribution of ASIC4 transcripts in the adult wild-type mouse brain. Neurosci Lett 2017; 651:57-64. [PMID: 28461138 DOI: 10.1016/j.neulet.2017.03.054] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 03/21/2017] [Accepted: 03/21/2017] [Indexed: 01/27/2023]
Abstract
Acid-sensing ion channel 4 (ASIC4) belongs to the ASIC gene family of neuronal proton-gated cation channels, and is the least understood subtype among the members. Previous studies of ASIC4 expression in the mammalian central nervous system have shown that ASIC4 is abundantly expressed in the spinal cord and in various brain regions, such as the cerebral cortex, the hippocampus, and the cerebellum. However, the detailed distribution of ASIC4 transcripts in mammalian brains still remains to be elucidated. In the present study, radioactive in situ hybridization histochemistry with an ASIC4-specific cRNA probe was performed on wild-type mouse brains, followed by X-gal staining experiments with Asic4-lacZ reporter mice Asic4tm1a(KOMP)Mbp. It was found that ASIC4 mRNAs were widely expressed throughout the wild-type brain, but preferentially concentrated in the olfactory bulb, the piriform cortex, the caudate putamen, the preoptic area, the paraventricular nucleus, the medial habenular nucleus, the pretectal area, the lateral geniculate nucleus, the amygdaloid complex, the superior colliculus, the interpeduncular nucleus, and the granule cell layer of the ventral hippocampus, and these results were in agreement with the X-gal-positive reactions observed in the mutant brain. In addition, X-gal staining combined with immunohistochemistry identified intense signals for ASIC4 transcriptional activity in most of the choline acetyltransferase (ChAT)-positive principal neurons located in the basal forebrain cholinergic nuclei. Our data provide useful information to speculate possible roles of ASIC4 in diverse brain functions.
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Affiliation(s)
- M Hoshikawa
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - A Kato
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - H Hojo
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - Y Shibata
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - N Kumamoto
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - M Watanabe
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - S Ugawa
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan.
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31
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Rash LD. Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future …. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 79:35-66. [PMID: 28528673 DOI: 10.1016/bs.apha.2017.02.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
pH is one of the most strictly controlled parameters in mammalian physiology. An extracellular pH of ~7.4 is crucial for normal physiological processes, and perturbations to this have profound effects on cell function. Acidic microenvironments occur in many physiological and pathological conditions, including inflammation, bone remodeling, ischemia, trauma, and intense synaptic activity. Cells exposed to these conditions respond in different ways, from tumor cells that thrive to neurons that are either suppressed or hyperactivated, often fatally. Acid-sensing ion channels (ASICs) are primary pH sensors in mammals and are expressed widely in neuronal and nonneuronal cells. There are six main subtypes of ASICs in rodents that can form homo- or heteromeric channels resulting in many potential combinations. ASICs are present and activated under all of the conditions mentioned earlier, suggesting that they play an important role in how cells respond to acidosis. Compared to many other ion channel families, ASICs were relatively recently discovered-1997-and there is a substantial lack of potent, subtype-selective ligands that can be used to elucidate their structural and functional properties. In this chapter I cover the history of ASIC channel pharmacology, which began before the proteins were even identified, and describe the current arsenal of tools available, their limitations, and take a glance into the future to predict from where new tools are likely to emerge.
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Affiliation(s)
- Lachlan D Rash
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia.
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32
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Boscardin E, Alijevic O, Hummler E, Frateschi S, Kellenberger S. The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19. Br J Pharmacol 2016; 173:2671-701. [PMID: 27278329 DOI: 10.1111/bph.13533] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 05/19/2016] [Accepted: 06/02/2016] [Indexed: 12/30/2022] Open
Abstract
Acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC) are both members of the ENaC/degenerin family of amiloride-sensitive Na(+) channels. ASICs act as proton sensors in the nervous system where they contribute, besides other roles, to fear behaviour, learning and pain sensation. ENaC mediates Na(+) reabsorption across epithelia of the distal kidney and colon and of the airways. ENaC is a clinically used drug target in the context of hypertension and cystic fibrosis, while ASIC is an interesting potential target. Following a brief introduction, here we will review selected aspects of ASIC and ENaC function. We discuss the origin and nature of pH changes in the brain and the involvement of ASICs in synaptic signalling. We expose how in the peripheral nervous system, ASICs cover together with other ion channels a wide pH range as proton sensors. We introduce the mechanisms of aldosterone-dependent ENaC regulation and the evidence for an aldosterone-independent control of ENaC activity, such as regulation by dietary K(+) . We then provide an overview of the regulation of ENaC by proteases, a topic of increasing interest over the past few years. In spite of the profound differences in the physiological and pathological roles of ASICs and ENaC, these channels share many basic functional and structural properties. It is likely that further research will identify physiological contexts in which ASICs and ENaC have similar or overlapping roles.
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Affiliation(s)
- Emilie Boscardin
- Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
| | - Omar Alijevic
- Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
| | - Edith Hummler
- Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
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33
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Marra S, Ferru-Clément R, Breuil V, Delaunay A, Christin M, Friend V, Sebille S, Cognard C, Ferreira T, Roux C, Euller-Ziegler L, Noel J, Lingueglia E, Deval E. Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids. EMBO J 2016; 35:414-28. [PMID: 26772186 DOI: 10.15252/embj.201592335] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 12/07/2015] [Indexed: 12/21/2022] Open
Abstract
Extracellular pH variations are seen as the principal endogenous signal that triggers activation of Acid-Sensing Ion Channels (ASICs), which are basically considered as proton sensors, and are involved in various processes associated with tissue acidification. Here, we show that human painful inflammatory exudates, displaying non-acidic pH, induce a slow constitutive activation of human ASIC3 channels. This effect is largely driven by lipids, and we identify lysophosphatidylcholine (LPC) and arachidonic acid (AA) as endogenous activators of ASIC3 in the absence of any extracellular acidification. The combination of LPC and AA evokes robust depolarizing current in DRG neurons at physiological pH 7.4, increases nociceptive C-fiber firing, and induces pain behavior in rats, effects that are all prevented by ASIC3 blockers. Lipid-induced pain is also significantly reduced in ASIC3 knockout mice. These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid-mediated signaling.
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Affiliation(s)
- Sébastien Marra
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
| | - Romain Ferru-Clément
- CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France
| | | | - Anne Delaunay
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
| | - Marine Christin
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
| | - Valérie Friend
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
| | - Stéphane Sebille
- CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France
| | - Christian Cognard
- CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France
| | - Thierry Ferreira
- CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France
| | | | | | - Jacques Noel
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
| | - Eric Lingueglia
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
| | - Emmanuel Deval
- CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France
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Wu J, Xu Y, Jiang YQ, Xu J, Hu Y, Zha XM. ASIC subunit ratio and differential surface trafficking in the brain. Mol Brain 2016; 9:4. [PMID: 26746198 PMCID: PMC4706662 DOI: 10.1186/s13041-016-0185-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 01/04/2016] [Indexed: 12/31/2022] Open
Abstract
Background Acid-sensing ion channels (ASICs) are key mediators of acidosis-induced responses in neurons. However, little is known about the relative abundance of different ASIC subunits in the brain. Such data are fundamental for interpreting the relative contribution of ASIC1a homomers and 1a/2 heteromers to acid signaling, and essential for designing therapeutic interventions to target these channels. We used a simple biochemical approach and semi-quantitatively determined the molar ratio of ASIC1a and 2 subunits in mouse brain. Further, we investigated differential surface trafficking of ASIC1a, ASIC2a, and ASIC2b. Results and conclusions ASIC1a subunits outnumber the sum of ASIC2a and ASIC2b. There is a region-specific variation in ASIC2a and 2b expression, with cerebellum and striatum expressing predominantly 2b and 2a, respectively. Further, we performed surface biotinylation and found that surface ASIC1a and ASIC2a ratio correlates with their total expression. In contrast, ASIC2b exhibits little surface presence in the brain. This result is consistent with increased co-localization of ASIC2b with an ER marker in 3T3 cells. Our data are the first semi-quantitative determination of relative subunit ratio of various ASICs in the brain. The differential surface trafficking of ASICs suggests that the main functional ASICs in the brain are ASIC1a homomers and 1a/2a heteromers. This finding provides important insights into the relative contribution of various ASIC complexes to acid signaling in neurons.
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Affiliation(s)
- Junjun Wu
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. .,China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai, 201203, China.
| | - Yuanyuan Xu
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. .,School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
| | - Yu-Qing Jiang
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. .,Department of Urology, The Third Hospital of Hebei Medical University, Shijiazhuang, HeBei, China.
| | - Jiangping Xu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
| | - Youjia Hu
- China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai, 201203, China.
| | - Xiang-ming Zha
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA.
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McCarthy CA, Rash LD, Chassagnon IR, King GF, Widdop RE. PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a. Neuropharmacology 2015; 99:650-7. [DOI: 10.1016/j.neuropharm.2015.08.040] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 08/18/2015] [Accepted: 08/24/2015] [Indexed: 12/18/2022]
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Ghatak S, Banerjee A, Sikdar SK. Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain. J Physiol 2015; 594:59-81. [PMID: 26445100 DOI: 10.1113/jp270706] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 09/21/2015] [Indexed: 02/01/2023] Open
Abstract
KEY POINTS The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection. In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices. Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner. Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328. Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change. A rise in lactate concentration and the leak potassium channel TREK1 have been independently associated with cerebral ischaemia. Recent literature suggests lactate to be neuroprotective and TREK1 knockout mice show an increased sensitivity to brain and spinal cord ischaemia; however, the connecting link between the two is missing. Therefore we hypothesized that lactate might interact with TREK1 channels. In the present study, we show that lactate at ischaemic concentrations (15-30 mm) at pH 7.4 increases TREK1 current in CA1 stratum radiatum astrocytes and causes membrane hyperpolarization. We confirm the intracellular action of lactate on TREK1 in hippocampal slices using monocarboxylate transporter blockers and at single channel level in cell-free inside-out membrane patches. The intracellular effect of lactate on TREK1 is specific since other monocarboxylates such as pyruvate and acetate at pH 7.4 failed to increase TREK1 current. Deletion and point mutation experiments suggest that lactate decreases the longer close dwell time incrementally with increase in lactate concentration by interacting with the histidine residue at position 328 (H328) in the carboxy terminal domain of the TREK1 channel. The interaction of lactate with H328 is dependent on the charge on the histidine residue since isosteric mutation of H328 to glutamine did not show an increase in TREK1 channel activity with lactate. This is the first demonstration of a direct effect of lactate on ion channel activity. The action of lactate on the TREK1 channel signifies a separate neuroprotective mechanism in ischaemia since it was found to be independent of the effect of acidic pH on channel activity.
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Affiliation(s)
- Swagata Ghatak
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India
| | - Aditi Banerjee
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India
| | - Sujit Kumar Sikdar
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India
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Osmakov DI, Andreev YA, Kozlov SA. Acid-sensing ion channels and their modulators. BIOCHEMISTRY (MOSCOW) 2015; 79:1528-45. [PMID: 25749163 DOI: 10.1134/s0006297914130069] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
According to a modern look acid-sensing ion channels (ASICs) are one of the most important receptors that perceive pH change in the body. ASICs represent proton-gated Na+-selective channels, which are expressed in neurons of the central and peripheral nervous system. These channels are attracting attention of researchers around the world, as they are involved in various physiological processes in the body. Drop of pH may occur in tissues in norm (e.g. the accumulation of lactic acid, the release of protons upon ATP hydrolysis) and pathology (inflammation, ischemic stroke, tissue damage and seizure). These processes are accompanied by unpleasant pain sensations, which may be short-lived or can lead to chronic inflammatory diseases. Modulators of ASIC channels activity are potential candidates for new effective analgesic and neuroprotection drugs. This review summarizes available information about structure, function, and physiological role of ASIC channels. In addition a description of all known ligands of these channels and their practical relevance is provided.
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Affiliation(s)
- D I Osmakov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
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Quintana P, Soto D, Poirot O, Zonouzi M, Kellenberger S, Muller D, Chrast R, Cull-Candy SG. Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischaemia and acidosis in hippocampal CA1 neurons. J Physiol 2015; 593:4373-86. [PMID: 26174503 PMCID: PMC4594240 DOI: 10.1113/jp270701] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 07/08/2015] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS The hippocampal CA1 region is highly vulnerable to ischaemic stroke. Two forms of AMPA receptor (AMPAR) plasticity - an anoxic form of long-term potentiation and a delayed increase in Ca(2+) -permeable (CP) AMPARs - contribute to this susceptibility by increasing excitotoxicity. In CA1, the acid-sensing ion channel 1a (ASIC1a) is known to facilitate LTP and contribute to ischaemic acidotoxicity. We have examined the role of ASIC1a in AMPAR ischaemic plasticity in organotypic hippocampal slice cultures exposed to oxygen glucose deprivation (a model of ischaemic stroke), and in hippocampal pyramidal neuron cultures exposed to acidosis. We find that ASIC1a activation promotes both forms of AMPAR plasticity and that neuroprotection, by inhibiting ASIC1a, circumvents any further benefit of blocking CP-AMPARs. Our observations establish a new interaction between acidotoxicity and excitotoxicity, and provide insight into the role of ASIC1a and CP-AMPARs in neurodegeneration. Specifically, we propose that ASIC1a activation drives certain post-ischaemic forms of CP-AMPAR plasticity. ABSTRACT The CA1 region of the hippocampus is particularly vulnerable to ischaemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischaemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca(2+) -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a), which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischaemic neuronal death and to physiologically induced LTP. This raises the question does ASIC1a activation drive the post-ischaemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPNs) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischaemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischaemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.
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Affiliation(s)
- Patrice Quintana
- Department of Basic Neurosciences, University of Geneva, 1211 Geneva 4, Switzerland.,Department of Medical Genetics, University of Lausanne, 1005, Lausanne, Switzerland
| | - David Soto
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Olivier Poirot
- Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, WC1E 6BT, UK.,Department of Pharmacology and Toxicology, University of Lausanne, 1005, Lausanne, Switzerland.,Department of Medical Genetics, University of Lausanne, 1005, Lausanne, Switzerland
| | - Marzieh Zonouzi
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Stephan Kellenberger
- Department of Pharmacology and Toxicology, University of Lausanne, 1005, Lausanne, Switzerland
| | - Dominique Muller
- Department of Basic Neurosciences, University of Geneva, 1211 Geneva 4, Switzerland
| | - Roman Chrast
- Department of Medical Genetics, University of Lausanne, 1005, Lausanne, Switzerland
| | - Stuart G Cull-Candy
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
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Baron A, Lingueglia E. Pharmacology of acid-sensing ion channels – Physiological and therapeutical perspectives. Neuropharmacology 2015; 94:19-35. [DOI: 10.1016/j.neuropharm.2015.01.005] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 12/15/2014] [Accepted: 01/07/2015] [Indexed: 12/29/2022]
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Proton-induced currents in substantia gelatinosa neurons of the rat trigeminal subnucleus caudalis. Eur J Pharmacol 2015; 762:18-25. [PMID: 25962663 DOI: 10.1016/j.ejphar.2015.04.052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Revised: 04/30/2015] [Accepted: 04/30/2015] [Indexed: 11/20/2022]
Abstract
Acid-sensing ion channels (ASICs) are widely expressed in both the peripheral and central nervous system, and contribute to the modulation of central nociceptive transmission under both physiological and pathophysiological conditions. In this study, we characterized the proton-induced membrane currents in acutely isolated rat substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis using the whole cell patch-clamp technique. Exposure to acidic conditions (pH<6.5) induced the inward currents in a pH-dependent manner. Amiloride, a general ASIC antagonist, significantly blocked the proton-induced currents in a non-competitive manner. The pH 6.0-induced membrane current (IpH6.0) was greatly attenuated in the Na(+)-free external solution, and the reversal potential of the proton-induced currents was similar to the theoretical Na(+) equilibrium potential. The IpH6.0 was reciprocally potentiated by a lower extracellular Ca(2+) concentration. The modulation of IpH6.0 by divalent cations and other modulators suggests that the proton-induced currents are mediated by multiple types of ASIC subunits, including ASIC1a and ASIC2a. Multi-cell RT-PCR analysis revealed that SG neurons express these subunits. Exposure to a pH 6.0 solution directly depolarized the membrane potential, and generated a burst of action potentials in a current-clamp mode. This acidic pH-induced depolarization was significantly blocked by amiloride. The present results suggest that ASICs expressed on SG neurons play important roles in the regulation of nociceptive transmission from the orofacial tissues.
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Differential regulation of proton-sensitive ion channels by phospholipids: a comparative study between ASICs and TRPV1. PLoS One 2015; 10:e0122014. [PMID: 25781982 PMCID: PMC4362947 DOI: 10.1371/journal.pone.0122014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 02/05/2015] [Indexed: 12/31/2022] Open
Abstract
Protons are released in pain-generating pathological conditions such as inflammation, ischemic stroke, infection, and cancer. During normal synaptic activities, protons are thought to play a role in neurotransmission processes. Acid-sensing ion channels (ASICs) are typical proton sensors in the central nervous system (CNS) and the peripheral nervous system (PNS). In addition to ASICs, capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channels can also mediate proton-mediated pain signaling. In spite of their importance in perception of pH fluctuations, the regulatory mechanisms of these proton-sensitive ion channels still need to be further investigated. Here, we compared regulation of ASICs and TRPV1 by membrane phosphoinositides, which are general cofactors of many receptors and ion channels. We observed that ASICs do not require membrane phosphatidylinositol 4-phosphate (PI(4)P) or phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for their function. However, TRPV1 currents were inhibited by simultaneous breakdown of PI(4)P and PI(4,5)P2. By using a novel chimeric protein, CF-PTEN, that can specifically dephosphorylate at the D3 position of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), we also observed that neither ASICs nor TRPV1 activities were altered by depletion of PI(3,4,5)P3 in intact cells. Finally, we compared the effects of arachidonic acid (AA) on two proton-sensitive ion channels. We observed that AA potentiates the currents of both ASICs and TRPV1, but that they have different recovery aspects. In conclusion, ASICs and TRPV1 have different sensitivities toward membrane phospholipids, such as PI(4)P, PI(4,5)P2, and AA, although they have common roles as proton sensors. Further investigation about the complementary roles and respective contributions of ASICs and TRPV1 in proton-mediated signaling is necessary.
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de Ceglia R, Chaabane L, Biffi E, Bergamaschi A, Ferrigno G, Amadio S, Del Carro U, Mazzocchi N, Comi G, Bianchi V, Taverna S, Forti L, D'Adamo P, Martino G, Menegon A, Muzio L. Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate. Brain Behav Immun 2015; 45:263-76. [PMID: 25499583 DOI: 10.1016/j.bbi.2014.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 12/02/2014] [Accepted: 12/02/2014] [Indexed: 11/26/2022] Open
Abstract
Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection.
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Affiliation(s)
- Roberta de Ceglia
- Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy
| | - Linda Chaabane
- Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy; Department of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele University, Milan, Italy
| | - Emilia Biffi
- Neuroengineering and Medical Robotics Laboratory, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy; Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Andrea Bergamaschi
- Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy
| | - Giancarlo Ferrigno
- Neuroengineering and Medical Robotics Laboratory, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy
| | - Stefano Amadio
- Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Italy
| | - Ubaldo Del Carro
- Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Italy
| | - Nausicaa Mazzocchi
- Advanced Light and Electron Microscopy Bio-Imaging Centre, Experimental Imaging Centre, San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Giancarlo Comi
- Department of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele University, Milan, Italy
| | - Veronica Bianchi
- Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy
| | - Stefano Taverna
- Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Lia Forti
- Center for Neuroscience and Dept. of Theoretical and Applied Sciences, Biomedical Division, University of Insubria, 21052 Busto Arsizio, Italy
| | - Patrizia D'Adamo
- Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy
| | - Gianvito Martino
- Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
| | - Andrea Menegon
- Advanced Light and Electron Microscopy Bio-Imaging Centre, Experimental Imaging Centre, San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Luca Muzio
- Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
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Vig PJS, Hearst SM, Shao Q, Lopez ME. Knockdown of acid-sensing ion channel 1a (ASIC1a) suppresses disease phenotype in SCA1 mouse model. THE CEREBELLUM 2015; 13:479-90. [PMID: 24788087 DOI: 10.1007/s12311-014-0563-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The mutated ataxin-1 protein in spinocerebellar ataxia 1 (SCA1) targets Purkinje cells (PCs) of the cerebellum and causes progressive ataxia due to loss of PCs and neurons of the brainstem. The exact mechanism of this cellular loss is still not clear. Currently, there are no treatments for SCA1; however, understanding of the mechanisms that regulate SCA1 pathology is essential for devising new therapies for SCA1 patients. We previously established a connection between the loss of intracellular calcium-buffering and calcium-signalling proteins with initiation of neurodegeneration in SCA1 transgenic (Tg) mice. Recently, acid-sensing ion channel 1a (ASIC1a) have been implicated in calcium-mediated toxicity in many brain disorders. Here, we report generating SCA1 Tg mice in the ASIC1a knockout (KO) background and demonstrate that the deletion of ASIC1a gene expression causes suppression of the SCA1 disease phenotype. Loss of the ASIC1a channel in SCA1/ASIC1a KO mice resulted in the improvement of motor deficit and decreased PC degeneration. Interestingly, the expression of the ASIC1 variant, ASIC1b, was upregulated in the cerebellum of both SCA1/ASIC1a KO and ASIC1a KO animals as compared to the wild-type (WT) and SCA1 Tg mice. Further, these SCA1/ASIC1a KO mice exhibited translocation of PC calcium-binding protein calbindin-D28k from the nucleus to the cytosol in young animals, which otherwise have both cytosolic and nuclear localization. Furthermore, in addition to higher expression of calcium-buffering protein parvalbumin, PCs of the older SCA1/ASIC1a KO mice showed a decrease in morphologic abnormalities as compared to the age-matched SCA1 animals. Our data suggest that ASIC1a may be a mediator of SCA1 pathogenesis and targeting ASIC1a could be a novel approach to treat SCA1.
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Affiliation(s)
- Parminder J S Vig
- Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA,
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Vick JS, Askwith CC. ASICs and neuropeptides. Neuropharmacology 2015; 94:36-41. [PMID: 25592215 DOI: 10.1016/j.neuropharm.2014.12.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 12/04/2014] [Accepted: 12/08/2014] [Indexed: 11/30/2022]
Abstract
The acid sensing ion channels (ASICs) are proton-gated cation channels expressed throughout the nervous system. ASICs are activated during acidic pH fluctuations, and recent work suggests that they are involved in excitatory synaptic transmission. ASICs can also induce neuronal degeneration and death during pathological extracellular acidosis caused by ischemia, autoimmune inflammation, and traumatic injury. Many endogenous neuromodulators target ASICs to affect their biophysical characteristics and contributions to neuronal activity. One of the most unconventional types of modulation occurs with the interaction of ASICs and neuropeptides. Collectively, FMRFamide-related peptides and dynorphins potentiate ASIC activity by decreasing the proton-sensitivity of steady state desensitization independent of G protein-coupled receptor activation. By decreasing the proton-sensitivity of steady state desensitization, the FMRFamide-related peptides and dynorphins permit ASICs to remain active at more acidic basal pH. Unlike the dynorphins, some FMRFamide-related peptides also potentiate ASIC activity by slowing inactivation and increasing the sustained current. Through mechanistic studies, the modulation of ASICs by FMRFamide-related peptides and dynorphins appears to be through distinct interactions with the extracellular domain of ASICs. Dynorphins are expressed throughout the nervous system and can increase neuronal death during prolonged extracellular acidosis, suggesting that the interaction between dynorphins and ASICs may have important consequences for the prevention of neurological injury. The overlap in expression of FMRFamide-related peptides with ASICs in the dorsal horn of the spinal cord suggests that their interaction may have important consequences for the treatment of pain during injury and inflammation. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.
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Affiliation(s)
- Jonathan S Vick
- The Department of Neuroscience, The Ohio State University Wexner Medical Center, United States
| | - Candice C Askwith
- The Department of Neuroscience, The Ohio State University Wexner Medical Center, United States.
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Kellenberger S, Schild L. International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol Rev 2015; 67:1-35. [PMID: 25287517 DOI: 10.1124/pr.114.009225] [Citation(s) in RCA: 210] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.
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Affiliation(s)
- Stephan Kellenberger
- Département de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland
| | - Laurent Schild
- Département de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland
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Du J, Reznikov LR, Welsh MJ. Expression and activity of acid-sensing ion channels in the mouse anterior pituitary. PLoS One 2014; 9:e115310. [PMID: 25506946 PMCID: PMC4266673 DOI: 10.1371/journal.pone.0115310] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 11/21/2014] [Indexed: 12/20/2022] Open
Abstract
Acid sensing ion channels (ASICs) are proton-gated cation channels that are expressed in the nervous system and play an important role in fear learning and memory. The function of ASICs in the pituitary, an endocrine gland that contributes to emotions, is unknown. We sought to investigate which ASIC subunits were present in the pituitary and found mRNA expression for all ASIC isoforms, including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3 and ASIC4. We also observed acid-evoked ASIC-like currents in isolated anterior pituitary cells that were absent in mice lacking ASIC1a. The biophysical properties and the responses to PcTx1, amiloride, Ca2+ and Zn2+ suggested that ASIC currents were mediated predominantly by heteromultimeric channels that contained ASIC1a and ASIC2a or ASIC2b. ASIC currents were also sensitive to FMRFamide (Phe-Met-Arg-Phe amide), suggesting that FMRFamide-like compounds might endogenously regulate pituitary ASICs. To determine whether ASICs might regulate pituitary cell function, we applied low pH and found that it increased the intracellular Ca2+ concentration. These data suggest that ASIC channels are present and functionally active in anterior pituitary cells and may therefore influence their function.
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Affiliation(s)
- Jianyang Du
- Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
- Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
| | - Leah R. Reznikov
- Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
| | - Michael J. Welsh
- Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
- Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
- Department of Molecular Physiology and Biophysics, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
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Tikhonova TB, Nagaeva EI, Barygin OI, Potapieva NN, Bolshakov KV, Tikhonov DB. Monoamine NMDA receptor channel blockers inhibit and potentiate native and recombinant proton-gated ion channels. Neuropharmacology 2014; 89:1-10. [PMID: 25196733 DOI: 10.1016/j.neuropharm.2014.08.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 07/15/2014] [Accepted: 08/26/2014] [Indexed: 10/24/2022]
Abstract
Acid-sensing ion channels (ASICs) are widely distributed in the peripheral and central nervous system. Although they are involved in many physiological functions, the actual processes that activate ASICs remain unclear. This is particularly true for brain ASICs, which produce only a transient response to a fast drop in pH and cannot mediate sustained current. Therefore, the search for ASIC inhibitors and, especially, potentiators/activators is important. We report that NMDA receptor channel blockers with a comparatively simple structure (9-aminoacridine, memantine, IEM-2117 and IEM-1921) potentiate and/or inhibit ASICs in submillimolar concentrations. The experiments were performed using the patch clamp technique on native ASICs from rat hippocampal interneurons and recombinant ASICs of different subunit compositions expressed in CHO cells. Native ASICs were potentiated by IEM-1921 and IEM-2117, and inhibited by memantine and 9-aminoacridine. Homomeric ASIC1a were inhibited by memantine, IEM-2117 and 9-aminoacridine while IEM-1921 was ineffective. In contrast, homomeric ASIC2a were potentiated by IEM-2117, memantine and IEM-1921, whereas 9-aminoacridine was inactive. The compounds caused a complex effect on ASIC3. 9-aminoacridine and IEM-1921 potentiated the steady-state response of ASIC3 and inhibited the peak component. IEM-2117 not only potentiated ASIC3-mediated currents caused by acidification but also evoked steady-state currents at neutral pH. Our results demonstrate that, depending on the subunit composition, ASICs can be activated or inhibited by simple compounds that possess only amino group and aromatic/hydrophobic moieties. This opens up the possibility to search for new ASIC modulators among a number of endogenous ligands.
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Affiliation(s)
- Tatiana B Tikhonova
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, 44 Thorez pr., St.Petersburg, Russia
| | - Elina I Nagaeva
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, 44 Thorez pr., St.Petersburg, Russia
| | - Oleg I Barygin
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, 44 Thorez pr., St.Petersburg, Russia
| | - Natalia N Potapieva
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, 44 Thorez pr., St.Petersburg, Russia
| | - Konstantin V Bolshakov
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, 44 Thorez pr., St.Petersburg, Russia
| | - Denis B Tikhonov
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, 44 Thorez pr., St.Petersburg, Russia.
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Su YS, Sun WH, Chen CC. Molecular mechanism of inflammatory pain. World J Anesthesiol 2014; 3:71-81. [DOI: 10.5313/wja.v3.i1.71] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 09/20/2013] [Accepted: 11/03/2013] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammatory pain resulting from arthritis, nerve injury and tumor growth is a serious public health issue. One of the major challenges in chronic inflammatory pain research is to develop new pharmacologic treatments with long-term efficacy and few side effects. The mediators released from inflamed sites induce complex changes in peripheral and central processing by directly acting on transducer receptors located on primary sensory neurons to transmit pain signals or indirectly modulating pain signals by activating receptors coupled with G-proteins and second messengers. High local proton concentration (acidosis) is thought to be a decisive factor in inflammatory pain and other mediators such as prostaglandin, bradykinin, and serotonin enhance proton-induced pain. Proton-sensing ion channels [transient receptor potential V1 (TRPV1) and the acid-sensing ion channel (ASIC) family] are major receptors for direct excitation of nociceptive sensory neurons in response to acidosis or inflammation. G-protein-coupled receptors activated by prostaglandin, bradykinin, serotonin, and proton modulate functions of TRPV1, ASICs or other ion channels, thus leading to inflammation- or acidosis-linked hyperalgesia. Although detailed mechanisms remain unsolved, clearly different types of pain or hyperalgesia could be due to complex interactions between a distinct subset of inflammatory mediator receptors expressed in a subset of nociceptors. This review describes new directions for the development of novel therapeutic treatments in pain.
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Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke? Prog Neurobiol 2014; 115:189-209. [PMID: 24467911 DOI: 10.1016/j.pneurobio.2013.12.008] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 11/28/2013] [Accepted: 12/24/2013] [Indexed: 12/13/2022]
Abstract
Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na(+)/H(+) exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H(+)-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca(2+), Na(+), and Zn(2+), and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention.
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Kweon HJ, Suh BC. Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation. BMB Rep 2014; 46:295-304. [PMID: 23790972 PMCID: PMC4133903 DOI: 10.5483/bmbrep.2013.46.6.121] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn2+, and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel’s large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-HT2. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated. [BMB Reports 2013; 46(6): 295-304]
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Affiliation(s)
- Hae-Jin Kweon
- Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Korea
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