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Nat Struct Mol Biol. 2008 Apr;15(4):403-10. doi: 10.1038/nsmb.1398. Epub 2008 Mar 16.

Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain.

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Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.


Increasing evidence suggests that intracellular H+ directly stimulates large-conductance Ca2+- and voltage-activated K+ (SLO1 BK) channels, thus providing a crucial link between membrane excitability and cell metabolism. Here we report that two histidine residues, His365 and His394, located in the intracellular regulator of conductance for K+ (RCK) 1 domain, serve as the H+ sensors of the SLO1 BK channel. Activation of the channel by H+ requires electrostatic interactions between the histidine residues and a nearby negatively charged residue involved in the channel's high-affinity Ca2+ sensitivity. Reciprocally, His365 and His394 also participate in the Ca2+-dependent activation of the channel, functioning as Ca2+ mimetics once they are protonated. Therefore, a common motif in the RCK1 domain mediates the stimulatory effects of both H+ and Ca2+, and provides a basis for the bidirectional coupling of cell metabolism and membrane electrical excitability.

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