Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade.
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+).
Immke
David C
DC
Vollum Institute, Oregon Health and Science University, Portland, OR 97201, USA.
McCleskey
Edwin W
EW
D062565:Acid Sensing Ion Channels; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D011522:Protons; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011522:Protons; D015222:Sodium Channels; D019344:Lactic Acid; D002118:Calcium