title: Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain.
abstract: 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.
authors.affiliation: Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shangwei
authors.initials: S
authors.lastname: Hou
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004331:Drosophila melanogaster; D006639:Histidine / Q000378:metabolism; D006801:Humans; D006859:Hydrogen / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009994:Osmolar Concentration; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D011994:Recombinant Proteins; D006639:Histidine; D006859:Hydrogen; D002118:Calcium