Journal
FASEB JOURNAL
Volume 32, Issue 11, Pages 6135-6149Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201800139R
Keywords
patch clamp; Slick; Slo2; 1; bithionol
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Funding
- U.S. National Institutes of Health General Medical Research [R01-GM087483]
- National Heart, Lung and Blood Institute [R01-HL071158]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01-AR-059646]
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Controversy surrounds the molecular identity of mitochondrial K+ channels that are important for protection against cardiac ischemia-reperfusion injury. Although K(Na)1.2 (sodium-activated potassium channel encoded by Kcn2) is necessary for cardioprotection by volatile anesthetics, electrophysiological evidence for a channel of this type in mitochondria is lacking. The endogenous physiological role of a potential mito-K(Na)1.2 channel is also unclear. In this study, single channel patch clamp of 27 independent cardiac mitochondrial inner membrane (mitoplast) preparations from wild-type (WT) mice yielded 6 channels matching the known ion sensitivity, ion selectivity, pharmacology, and conductance properties of K(Na)1.2 (slope conductance, 138 +/- 1 pS). However, similar experiments on 40 preparations from Kcnt2(-/-) mice yielded no such channels. The K-Na opener bithionol uncoupled respiration in WT but not Kcnt2(-/-) cardiomyocytes. Furthermore, when oxidizing only fat as substrate, Kcnt2(-/-) cardiomyocytes and hearts were less responsive to increases in energetic demand. Kcnt2(-/-) mice also had elevated body fat, but no baseline differences in the cardiac metabolome. These data support the existence of a cardiac mitochondrial K(Na)1.2 channel, and a role for cardiac K(Na)1.2 in regulating metabolism under conditions of high energetic demand.Smith, C. O., Wang, Y. T., Nadtochiy, S. M., Miller, J. H., Jonas, E. A., Dirksen, R. T., Nehrke, K., Brookes, P. S. Cardiac metabolic effects of K(Na)1.2 channel deletion and evidence for its mitochondrial localization.
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