ATP consumption by uncoupled mitochondria activates sarcolemmal KATP channels in cardiac myocytes

Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland 21205 We tested whether close coupling exists between mitochondria and sarcolemma by monitoring whole cell ATP-sensitive K + (K ATP ) current ( I K,ATP ) as an index of subsarcolemmal energy state during mitochondrial perturbation. In rabbit ventricular myocytes, either pinacidil or the mitochondrial uncoupler dinitrophenol (DNP), which rapidly switches mitochondria from net ATP synthesis to net ATP hydrolysis, had little immediate effect on I K,ATP . In contrast, in the presence of pinacidil, exposure to 100 µM DNP rapidly activated I K,ATP with complex kinetics consisting of a quick rise [time constant of I K,ATP increase ( ) = 0.13 ± 0.01 min], an early partial recovery ( = 0.43 ± 0.04 min), and then a more gradual increase. This DNP-induced activation of I K,ATP was reversible and accompanied by mitochondrial flavoprotein oxidation. The F 1 F 0 -ATPase inhibitor oligomycin abolished the DNP-induced activation of I K,ATP . The initial rapid rise in I K,ATP was blunted by atractyloside (an adenine nucleotide translocator inhibitor), leaving only a slow increase ( = 0.66 ± 0.17 min, P