Abstract
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 microM). 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 approximately ATPgammaS approximately 2-methylthio-ATP (P2Y-selective) > ADP > alpha,betameATP (P2X-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 P2Y-specific Reactive Blue 2. Glucose transport inhibition by ATP was not affected by a drastic reduction of the extracellular concentrations of calcium (down to 10(-9) M) or sodium (down to 0 mM), and it was not mimicked by a potassium-induced depolarization, indicating that purinoceptors of the P2X 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 P2Y purinoceptor family.
Highlights
Other source of extracellular ATP is that released from parenchymal cells under hypoxic or ischemic conditions [3]
More recent studies using isolated cardiomyocytes have shown that micromolar levels of extracellular ATP increase (i) plasma membrane conductances for cations [9] and for chloride [10, 11], (ii) the cytosolic calcium concentration [9, 12,13,14,15], (iii) the rate of phosphoinositide hydrolysis [14, 16, 17], and (iv) the contraction amplitude [12, 14, 15]
In an initial series of experiments, we investigated the action of purinergic agonists on cardiomyocyte glucose transport
Summary
Other source of extracellular ATP is that released from parenchymal cells under hypoxic or ischemic conditions [3]. More recent studies using isolated cardiomyocytes have shown that micromolar levels of extracellular ATP increase (i) plasma membrane conductances for cations [9] and for chloride [10, 11], (ii) the cytosolic calcium concentration [9, 12,13,14,15], (iii) the rate of phosphoinositide hydrolysis [14, 16, 17], and (iv) the contraction amplitude [12, 14, 15] These results, along with pharmacological and immunohistochemical data (10, 11, 13, 14, 18 –20), suggest that members of both families of P2 receptors are expressed in and linked to the electrical and contractile function of cardiac muscle cells. We observed a pronounced inhibitory action of purinergic agonists on the rate of glucose transport and explored the underlying mechanisms
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