Abstract
Acid-sensing ion channels (ASICs) open when extracellular pH drops and they are enhanced by lactate, making them specialized for detecting lactic acidosis. Highly expressed on cardiac nociceptors and some other sensory neurons, ASICs may help trigger pain caused by tissue ischemia. We report that H(+) opens ASIC3 by speeding release of Ca(2+) from a high-affinity binding site (K(Ca) = 150 nM) on the extracellular side of the pore. The bound Ca(2+) blocks permeation and the channel conducts when multiple H(+) ions relieve this block. Activation through Ca(2+) explains sensitivity to lactate, which decreases extracellular [Ca(2+)], and it may prove relevant in CNS pathologies (stroke, seizure) that simultaneously drop pH and Ca(2+).
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acid Sensing Ion Channels
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Animals
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Binding Sites / drug effects
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Binding Sites / physiology
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COS Cells
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Calcium / metabolism*
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Catalytic Domain / drug effects
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Catalytic Domain / physiology
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Cell Membrane / drug effects
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Cell Membrane / metabolism*
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Cell Membrane Permeability / drug effects
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Cell Membrane Permeability / physiology
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Chemoreceptor Cells / drug effects
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Chemoreceptor Cells / metabolism*
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Hydrogen-Ion Concentration
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Ion Channel Gating / drug effects
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Ion Channel Gating / physiology
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Kinetics
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Lactic Acid / metabolism
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Membrane Proteins*
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Nerve Tissue Proteins*
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Neurons, Afferent / drug effects
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Neurons, Afferent / metabolism*
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Protons*
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Sodium Channels / drug effects
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Sodium Channels / metabolism*
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Stereoisomerism
Substances
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ASIC3 protein, human
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Acid Sensing Ion Channels
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Membrane Proteins
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Nerve Tissue Proteins
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Protons
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Sodium Channels
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Lactic Acid
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Calcium