© 1997 American Heart Association, Inc.
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Enhancement of the ATP-Sensitive K+ Current by Extracellular ATP in Rat Ventricular Myocytes
Involvement of Adenylyl Cyclase–Induced Subsarcolemmal ATP Depletion
From INSERM U-390, Physiopathologie Cardiovasculaire, Montpellier, France.
Correspondence to Dr Guy Vassort, INSERM U-390, Physiopathologie Cardiovasculaire, CHU Arnaud de Villeneuve, F-34295 Montpellier Cedex 05, France. E-mail vassort{at}u390.montp.inserm.fr
Abstract ATP-sensitive K+ (KATP) channels are present at high density in membranes of cardiac cells, where they regulate cardiac function during metabolic impairment. The present study analyzes the effects of extracellular ATP (ATPe), a P2-purinergic agonist that can be released under various conditions in the myocardial cell bed, on KATP current (IK-ATP) in rat ventricular myocytes. Under the whole-cell patch-clamp configuration at a physiological level of intracellular ATP, applying ATPe in the micromolar range did not activate IK-ATP. However, dialyzing the cell with a low-ATP (100 µmol/L) pipette solution elicited a slowly, quasilinearly increasing IK-ATP that was markedly enhanced by applying ATPe in the presence of a P1-purinergic antagonist. The effect was reversible on washing out the agonist. The IK-ATP enhancement was inhibited by cholera toxin treatment of the myocytes, suggesting that a Gs protein was involved to mediate the effect. Experiments on excised patches allowed us to exclude a membrane-delimited G protein–dependent pathway. Rather, the results suggested that ATPe activates the adenylyl cyclase, since its inhibition by 2'-deoxyadenosine 3'-monophosphate and SQ-22536, which respectively interact with the purine and catalytic site of the cyclase, strongly reduced the ATPe-induced IK-ATP enhancement, whereas neither compound affected IK-ATP in inside-out patches. Inhibition of cAMP-dependent protein kinase by protein kinase inhibitor peptide 5-24 did not alter the purinergic effect. The findings suggests that ATPe triggers the activation of adenylyl cyclase, which causes a subsarcolemmal ATP depletion sufficient to enhance IK-ATP as it develops during low-ATP dialysis of rat ventricular myocytes.
Key Words: ATP-sensitive K+ channel • purinergic stimulation • G protein • adenylyl cyclase • ATP depletion
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