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J Biol Chem, Vol. 274, Issue 2, 755-761, January 8, 1999

Purinergic Inhibition of Glucose Transport in Cardiomyocytes

From the Institute of Physiology, Medical Faculty, Pauwelsstrasse 30, D-52057 Aachen, Germany

ATP is known to act as an extracellular signal in many organs. In the heart, extracellular ATP modulates ionic processes and contractile function. This study describes a novel, metabolic effect of exogenous ATP in isolated rat cardiomyocytes. In these quiescent (i.e. noncontracting) cells, micromolar concentrations of ATP depressed the rate of basal, catecholamine-stimulated, or insulin-stimulated glucose transport by up to 60% (IC₅₀ for inhibition of insulin-dependent glucose transport, 4 µM). ATP decreased the amount of glucose transporters (GLUT1 and GLUT4) in the plasma membrane, with a concomitant increase in intracellular microsomal membranes. A similar glucose transport inhibition was produced by P₂ purinergic agonists with the following rank of potencies: ATP  ATPS  2-methylthio-ATP (P_2Y-selective) > ADP > ,meATP (P_2X-selective), whereas the P₁ purinoceptor agonist adenosine was ineffective. The effect of ATP was suppressed by the poorly subtype-selective P₂ antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid but, surprisingly, not by the nonselective antagonist suramin nor by the P_2Y-specific Reactive Blue 2. Glucose transport inhibition by ATP was not affected by a drastic reduction of the extracellular concentrations of calcium (down to 10⁹ M) or sodium (down to 0 mM), and it was not mimicked by a potassium-induced depolarization, indicating that purinoceptors of the P_2X family (which are nonselective cation channels whose activation leads to a depolarizing sodium and calcium influx) are not involved. Inhibition was specific for the transmembrane transport of glucose because ATP did not inhibit (i) the rate of glycolysis under conditions where the transport step is no longer rate-limiting nor (ii) the rate of [1-¹⁴C]pyruvate decarboxylation. In conclusion, extracellular ATP markedly inhibits glucose transport in rat cardiomyocytes by promoting a redistribution of glucose transporters from the cell surface to an intracellular compartment. This effect of ATP is mediated by P₂ purinoceptors, possibly by a yet unknown subtype of the P_2Y purinoceptor family.

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