Dual role of acid-sensing ion channels 3 in rheumatoid arthritis: destruction or protection?

Acid-sensing ion channels (ASICs) are proton-gated Na+ channels. Being almost ubiquitously present in neurons of the vertebrate nervous system, their precise function remained obscure for a long time. Various animal toxins that bind to ASICs with high affinity and specificity have been tremendously helpful in uncovering the role of ASICs. We now know that they contribute to synaptic transmission at excitatory synapses as well as to sensing metabolic acidosis and nociception. Moreover, detailed characterization of mouse models uncovered an unanticipated role of ASICs in disorders of the nervous system like stroke, multiple sclerosis, and pathological pain. This review provides an overview on the expression, structure, and pharmacology of ASICs plus a summary of what is known and what is still unknown about their physiological functions and their roles in diseases.

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Dual Role of Autophagy in Stress-Induced Cell Death in Rheumatoid Arthritis Synovial Fibroblasts

Arthritis & Rheumatology ◽

10.1002/art.38190 ◽

2013 ◽

Vol 66 (1) ◽

pp. 40-48 ◽

Cited By ~ 69

Author(s):

Masaru Kato ◽

Caroline Ospelt ◽

Renate E. Gay ◽

Steffen Gay ◽

Kerstin Klein

Keyword(s):

Rheumatoid Arthritis ◽

Cell Death ◽

Synovial Fibroblasts ◽

Dual Role

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Acid-sensing ion channels in sensory signaling

AJP Renal Physiology ◽

10.1152/ajprenal.00546.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. F531-F543 ◽

Cited By ~ 1

Author(s):

Marcelo D. Carattino ◽

Nicolas Montalbetti

Keyword(s):

Nervous System ◽

Ion Channels ◽

Peripheral Nervous System ◽

Sensory Neurons ◽

Genetically Modified ◽

Physiological Processes ◽

Acid Sensing Ion Channels ◽

Genetically Modified Mice ◽

Sensory Processes

Acid-sensing ion channels (ASICs) are cation-permeable channels that in the periphery are primarily expressed in sensory neurons that innervate tissues and organs. Soon after the cloning of the ASIC subunits, almost 20 yr ago, investigators began to use genetically modified mice to assess the role of these channels in physiological processes. These studies provide critical insights about the participation of ASICs in sensory processes, including mechanotransduction, chemoreception, and nociception. Here, we provide an extensive assessment of these findings and discuss the current gaps in knowledge with regard to the functions of ASICs in the peripheral nervous system.

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Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0431 ◽

2016 ◽

Vol 371 (1700) ◽

pp. 20150431 ◽

Cited By ~ 13

Author(s):

O. Ievglevskyi ◽

D. Isaev ◽

O. Netsyk ◽

A. Romanov ◽

M. Fedoriuk ◽

...

Keyword(s):

Ion Channels ◽

Hippocampal Neurons ◽

Hippocampal Slices ◽

Synaptic Activity ◽

Mammalian Brain ◽

Strong Increase ◽

Life And Death ◽

Acid Sensing Ion Channels

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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The role of acid-sensing ion channels in epithelial Na+ uptake in adult zebrafish (Danio rerio)

Journal of Experimental Biology ◽

10.1242/jeb.113118 ◽

2015 ◽

Vol 218 (8) ◽

pp. 1244-1251 ◽

Cited By ~ 28

Author(s):

A. K. Dymowska ◽

D. Boyle ◽

A. G. Schultz ◽

G. G. Goss

Keyword(s):

Ion Channels ◽

Danio Rerio ◽

Adult Zebrafish ◽

Acid Sensing Ion Channels ◽

Na Uptake

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Conserved His-Gly motif of acid-sensing ion channels resides in a reentrant ‘loop’ implicated in gating and ion selectivity

10.1101/2020.03.02.974154 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nate Yoder ◽

Eric Gouaux

Keyword(s):

Ion Channels ◽

Ion Selectivity ◽

Fear Memory ◽

Amino Terminus ◽

Ion Permeation ◽

Structural Explanation ◽

Cryo Electron Microscopy ◽

Acid Sensing Ion Channels ◽

And Function

ABSTRACTAcid-sensing ion channels (ASICs) are proton-gated members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout central and peripheral nervous systems. The homotrimeric splice variant ASIC1a has been implicated in nociception, fear memory, mood disorders and ischemia. Here we extract full-length chicken ASIC1a (cASIC1a) from cell membranes using styrene maleic acid (SMA) copolymer, yielding structures of ASIC1a channels in both high pH resting and low pH desensitized conformations by single-particle cryo-electron microscopy (cryo-EM). The structures of resting and desensitized channels reveal a reentrant loop at the amino terminus of ASIC1a that includes the highly conserved ‘His-Gly’ (HG) motif. The reentrant loop lines the lower ion permeation pathway and buttresses the ‘Gly-Ala-Ser’ (GAS) constriction, thus providing a structural explanation for the role of the His-Gly dipeptide in the structure and function of ASICs.

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Role of Acid-sensing Ion Channels (ASICs) in the Vascular Endothelial Cells Injury of Henoch- Schonlein Purpura Children

International Journal of Clinical & Medical Allergy ◽

10.19070/2332-2799-1600010 ◽

2016 ◽

pp. 44-51 ◽

Cited By ~ 1

Author(s):

Qi-di Peng ◽

◽

Yuan LP ◽

Yan B ◽

Guo XY ◽

...

Keyword(s):

Endothelial Cells ◽

Ion Channels ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Henoch Schonlein Purpura ◽

Acid Sensing Ion Channels ◽

Schonlein Purpura ◽

Henoch Schönlein Purpura

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Role of Transient Receptor Potential and Acid-sensing Ion Channels in Peripheral Inflammatory Pain

Anesthesiology ◽

10.1097/aln.0b013e3181ca3179 ◽

2010 ◽

Vol 112 (3) ◽

pp. 729-741 ◽

Cited By ~ 23

Author(s):

John P. M. White ◽

Mario Cibelli ◽

Antonio Rei Fidalgo ◽

Cleoper C. Paule ◽

Faruq Noormohamed ◽

...

Keyword(s):

Ion Channels ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Ionotropic Receptors ◽

Acid Sensing Ion Channels ◽

Peripheral Pain ◽

Transient Receptor

Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body's response to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions-as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation.

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