Acid-sensing ion channels: advances, questions and therapeutic opportunities

Wemmie, John A.; Price, Margaret P.; Welsh, Michael J.

doi:10.1016/j.tins.2006.06.014

Cited by 503 publications

(552 citation statements)

References 105 publications

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“…In mammals, there is a defined, although not absolute, specificity of the distribution of various ASIC subtypes between the central nervous system (CNS) and peripheral nervous system (PNS). ASIC1a, ASIC2a, and ASIC2b are expressed in both PNS and CNS, while ASIC1b and ASIC3 are primarily expressed in sensory neurons (4,5). As the most sensitive ASIC subtype to extracellular pH, the widespread distribution of ASIC3 is consistent with its role as key receptors for extracellular protons in peripheral tissues.…”

Section: Introductionmentioning

confidence: 71%

“…The rapid desensitization kinetics often calls into question the long-lasting physiological roles of ASICs (4,5). ASIC3, however, is well suited to play a long-lasting physiological role because it mediates a sustained current (Figure 2, panel c) that does not fully desensitize during the continued presence of acidic extracellular pH (9)(10)(11)(12).…”

Section: Sustained Activation and Window Currentsmentioning

confidence: 99%

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ASIC3 Channels in Multimodal Sensory Perception

2010

ACS Chem. Neurosci.

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Acid-sensing ion channels (ASICs), which are members of the sodium-selective cation channels belonging to the epithelial sodium channel/degenerin (ENaC/ DEG) family, act as membrane-bound receptors for extracellular protons as well as nonproton ligands. At least five ASIC subunits have been identified in mammalian neurons, which form both homotrimeric and heterotrimeric channels. The highly proton sensitive ASIC3 channels are predominantly distributed in peripheral sensory neurons, correlating with their roles in multimodal sensory perception, including nociception, mechanosensation, and chemosensation. Different from other ASIC subunit composing ion channels, ASIC3 channels can mediate a sustained window current in response to mild extracellular acidosis (pH 7.3-6.7), which often occurs accompanied by many sensory stimuli. Furthermore, recent evidence indicates that the sustained component of ASIC3 currents can be enhanced by nonproton ligands including the endogenous metabolite agmatine. In this review, we first summarize the growing body of evidence for the involvement of ASIC3 channels in multimodal sensory perception and then discuss the potential mechanisms underlying ASIC3 activation and mediation of sensory perception, with a special emphasis on its role in nociception. We conclude that ASIC3 activation and modulation by diverse sensory stimuli represent a new avenue for understanding the role of ASIC3 channels in sensory perception. Furthermore, the emerging implications of ASIC3 channels in multiple sensory dysfunctions including nociception allow the development of new pharmacotherapy.

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Section: Introductionmentioning

confidence: 71%

Section: Sustained Activation and Window Currentsmentioning

confidence: 99%

ASIC3 Channels in Multimodal Sensory Perception

2010

ACS Chem. Neurosci.

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“…For decades, the entity or receptor that detects pH o changes surrounding neurons and its signal transduction pathway remained elusive. The recent finding that a fall of pH o activates a distinct class of cation channels, the acid-sensing ion channels (ASICs), in peripheral sensory neurons and in the neurons of the central nervous system, dramatically changed the view of acid signaling and offered new pharmacological targets for neurological diseases [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Xiong

Pignataro²,

et al. 2008

Current Opinion in Pharmacology

214

161

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A significant drop of tissue pH or acidosis is a common feature of acute neurological conditions such as ischemic stroke, brain trauma, and epileptic seizures. Acid-sensing ion channels, or ASICs, are proton-gated cation channels widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. Recent studies have demonstrated that activation of these channels by protons plays an important role in a variety of physiological and pathological processes such as nociception, mechanosensation, synaptic plasticity, and acidosis-mediated neuronal injury. This review provides an overview of the recent advance in electrophysiological, pharmacological characterization of ASICs, and their role in neurological diseases. Therapeutic potential of current available ASIC inhibitors is discussed.

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“…Nonetheless, we do not think that ENaC and ASICs are responsible for the G NH4 in ST‐1 because these two proteins are very sensitive to amiloride (Benos 1982; Wemmie et al. 2006). We found no amiloride sensitivity of the G NH4 .…”

Section: Discussionmentioning

confidence: 99%

Evidence for ammonium conductance in a mouse thick ascending limb cell line

Lee

Park

et al. 2017

Physiol Rep

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In this study, we examined an ammonium conductance in the mouse thick ascending limb cell line ST‐1. Whole cell patch clamp was performed to measure currents evoked by NH 4Cl in the presence of BaCl2, tetraethylammonium, and BAPTA. Application of 20 mmol/L NH 4Cl induced an inward current (−272 ± 79 pA, n = 9). In current‐voltage (I–V) relationships, NH 4Cl application caused the I–V curve to shift down in an inward direction. The difference in current before and after NH 4Cl application, which corresponds to the current evoked by NH 4Cl, was progressively larger at more negative potentials. The reversal potential for NH4Cl was +15 mV, higher than the equilibrium potential for chloride, indicating that the current should be due to NH 4 +. We then injected ST‐1 poly(A) RNA into Xenopus oocytes and performed two‐electrode voltage clamp. NH 4Cl application in the presence of BaCl2 caused the I–V curve to be steeper. The NH 4 + current was retained at pH 6.4, where endogenous oocyte current was abolished. The NH 4 + current was unaffected by 10 μmol/L amiloride but abolished after incubation in Na+‐free media. These results demonstrate that the renal cell line ST‐1 produces an NH 4 + conductance.

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Acid-sensing ion channels: advances, questions and therapeutic opportunities

Cited by 503 publications

References 105 publications

ASIC3 Channels in Multimodal Sensory Perception

ASIC3 Channels in Multimodal Sensory Perception

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Evidence for ammonium conductance in a mouse thick ascending limb cell line

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