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Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a.


Acid-sensing ion channels (ASICs) are H(+)-gated Na(+) channels, which are present in most, if not all, neurons. The typical ASIC current is transient and is elicited by a rapid drop in the extracellular pH. In the human genome, four genes for ASICs are present: asic1 - 4. In this review, we will focus on ASIC1a, one of the key subunits in the central nervous system. We will describe the structure of this channel, a topic that has enormously profited from the recent elucidation of the first crystal structure of an ASIC. We will then relate the ASIC1 structure to current models of the gating mechanism of ASICs. Finally, we will review the pharmacology of ASIC1a. Advances in the pharmacological inhibition of individual ASIC currents have greatly contributed to our current knowledge of the functional roles of this channel in physiology, including learning, memory, and fear conditioning, and in pathophysiological states, including the neurodegeneration accompanying stroke, and axonal degeneration in autoimmune inflammation.


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