Purinergic inhibition of glucose transport in cardiomyocytes

ATP is known to act as an extracellular signal in many organs. In the heart , extracellular ATP modulates ionic processes and contractile function. Thi s study describes a novel, metabolic effect of exogenous ATP in isolated ra t cardiomyocytes, In these quiescent (i.e. noncontracting) cells, micromola r concentrations of ATP depressed the rate of basal, catecholamine stimulat ed, or insulin-stimulated glucose transport by up to 60% (IC50 for inhibiti on of insulin-dependent glucose transport, 4 mu M). ATP decreased the amoun t of glucose transporters (GLUT1 and GLUT4) in the plasma membrane, with a concomitant increase in intracellular microsomal membranes. A similar gluco se transport inhibition was produced by P-2 purinergic agonists with the fo llowing rank of potencies: ATP approximate to ATP gamma S approximate to 2- methylthio-ATP (P-2Y-selective) > ADP > alpha,beta meATP (P-2X-selective), whereas the P-1 purinoceptor agonist adenosine was ineffective. The effect of ATP was suppressed by the poorly subtype-selective P-2 antagonist pyrido xal-phosphate-6-azophenyl-azophenyl-2',4'-disulfonic acid but, surprisingly , not by the nonselective antagonist suramin nor by the P-2Y-specific React ive flue 2. Glucose transport inhibition by ATP was not affected by a drast ic reduction of the extracellular concentrations of calcium (down to 10(-9) M) or so dium (down to 0 mM), and it was not mimicked by a potassium-induc ed depolarization, indicating that purinoceptors of the P-2X family (which are nonselective cation channels whose activation leads to a depolarizing s odium and calcium influx) are not involved. Inhibition was specific for the transmembrane transport of glucose because ATP did not inhibit (i) the rat e of glycolysis under conditions where the transport step is no longer rate -limiting nor (ii) the rate of [1-C-14]pyruvate decarboxylation. In conclus ion, extracellular ATP markedly inhibits glucose transport in rat cardiomyo cytes by promoting a redistribution of glucose transporters from the cell s urface to an intracellular compartment. This effect of ATP is mediated by P -2 purinoceptors, possibly by a yet unknown subtype of the P-2Y purinocepto r family.