title: The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels.
abstract: Carbon monoxide (CO) is a lethal gas, but it is also increasingly recognized as a physiological signaling molecule capable of regulating a variety of proteins. Among them, large-conductance Ca(2+)- and voltage-gated K(+) (Slo1 BK) channels, important in vasodilation and neuronal firing, have been suggested to be directly stimulated by CO. However, the molecular mechanism of the stimulatory action of CO on the Slo1 BK channel has not been clearly elucidated. We report here that CO reliably and repeatedly activates Slo1 BK channels in excised membrane patches in the absence of Ca(2+) in a voltage-sensor-independent manner. The stimulatory action of CO on the Slo1 BK channel requires an aspartic acid and two histidine residues located in the cytoplasmic RCK1 domain, and the effect persists under the conditions known to inhibit the conventional interaction between CO and heme in other proteins. We propose that CO acts as a partial agonist for the high-affinity divalent cation sensor in the RCK1 domain of the Slo1 BK channel.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 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: D002118:Calcium / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002460:Cell Line; D006427:Hemin / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D006427:Hemin; D002248:Carbon Monoxide; D002118:Calcium