title: SLO-2 is cytoprotective and contributes to mitochondrial potassium transport.
abstract: Mitochondrial potassium channels are important mediators of cell protection against stress. The mitochondrial large-conductance "big" K(+) channel (mBK) mediates the evolutionarily-conserved process of anesthetic preconditioning (APC), wherein exposure to volatile anesthetics initiates protection against ischemic injury. Despite the role of the mBK in cardioprotection, the molecular identity of the channel remains unknown. We investigated the attributes of the mBK using C. elegans and mouse genetic models coupled with measurements of mitochondrial K(+) transport and APC. The canonical Ca(2+)-activated BK (or "maxi-K") channel SLO1 was dispensable for both mitochondrial K(+) transport and APC in both organisms. Instead, we found that the related but physiologically-distinct K(+) channel SLO2 was required, and that SLO2-dependent mitochondrial K(+) transport was triggered directly by volatile anesthetics. In addition, a SLO2 channel activator mimicked the protective effects of volatile anesthetics. These findings suggest that SLO2 contributes to protection from hypoxic injury by increasing the permeability of the mitochondrial inner membrane to K(+).
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wojtovich
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Sherman
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: William R
authors.initials: WR
authors.lastname: Urciuoli
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.forename: Keith
authors.initials: K
authors.lastname: Nehrke
mesh_terms: D018685:Anesthetics, Inhalation; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019610:Cytoprotection; D000860:Hypoxia / Q000517:prevention & control*; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D017136:Ion Transport; D019157:Ischemic Preconditioning, Myocardial; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D029742:Caenorhabditis elegans Proteins; D007211:Indoles; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026901:Membrane Transport Proteins; D026902:Potassium Channel Blockers; C402625:SLO-2 protein, C elegans; C048220:paxilline