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Losing Calcium is a Pain

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Science's STKE  14 Jan 2003:
Vol. 2003, Issue 165, pp. tw19-TW19
DOI: 10.1126/stke.2003.165.tw19

Immke and McCleskey investigated Ca2+ modulation of acid-sensing ion channels (ASICs) and concluded that H+ and Ca2+ compete for a binding site so that increasing extracellular H+ catalyzed Ca2+ dissociation, unblocking the channel pore. ASICs, which allow Na+ into the cell in response to decreased extracellular pH, may contribute to ischemic pain during heart attacks. Lactate, which is released along with acid during muscle ischemia, increases the sensitivity of ASICs to extracellular H+ by decreasing extracellular Ca2+ concentration ([Ca2+]o). Immke and McCleskey used whole-cell patch-clamp of COS7 cells expressing ASIC3 to analyze currents elicited by decreasing pH at differing [Ca2+]o, currents elicited by decreasing [Ca2+]o at differing pH, and recovery from desensitization. Their data indicated that multiple H+ competed with a single Ca2+ for a binding site and that Ca2+ must dissociate before current can flow through the channel. Measurements of single-channel conductance in outside-out patches indicated that Ca2+ dissociation unblocked the channel pore, rather than triggering a change in channel conformation. Ca2+ binding appeared unaffected by membrane voltage or the direction of current flow, which suggests that the binding site was toward the extracellular side of the channel, rather than in the narrowest region of the pore. Because ACISs are found in the brain, as well as in sensory neurons, these data not only provide a mechanism for ASIC mediation of ischemic pain, but may also be relevant to pathological conditions in the brain--such as stroke and seizure--that involve decreases in extracellular pH and [Ca]o.

D. C. Immke, E. W. McCleskey, Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 37, 75-84 (2003). [Online Journal]

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