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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+ (KATP) current
(IK,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
IK,ATP. In contrast, in the presence of
pinacidil, exposure to 100 µM DNP rapidly activated
IK,ATP with complex kinetics consisting of a
quick rise [time constant of IK,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
IK,ATP was reversible and accompanied by
mitochondrial flavoprotein oxidation. The
F1F0-ATPase inhibitor oligomycin abolished the
DNP-induced activation of IK,ATP. The initial
rapid rise in IK,ATP was blunted by
atractyloside (an adenine nucleotide translocator inhibitor), leaving
only a slow increase ( = 0.66 ± 0.17 min,
P < 0.01). 2,4-Dinitrofluorobenzene (a creatine kinase
inhibitor) slowed both the rapid rise ( = 0.20 ± 0.01 min, P < 0.05) and the subsequent declining phase
( = 0.88 ± 0.19 min, P < 0.05). From
single KATP channel recordings, we excluded a direct effect
of DNP on KATP channels. Taken together, these results
indicate that rapid changes in F1F0-ATPase
function dramatically alter subsarcolemmal energy charge, as reported
by pinacidil-primed KATP channel activity, revealing
cross-talk between mitochondria and sarcolemma. The effects of
mitochondrial ATP hydrolysis on sarcolemmal KATP channels can be rationalized by reversal of F1F0-ATPase
and the facilitation of coupling by the creatine kinase system.
dinitrophenol; ATP hydrolysis; patch-clamp; ATP-sensitive K+ channels
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