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 insulinstimulated glucose transport by up to 60% (IC 50 for inhibition of insulin-dependent glucose transport, 4 M). 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 P 2 purinergic agonists with the following rank of potencies: ATP Ϸ ATP␥S Ϸ 2-methylthio-ATP (P 2Y -selective) > ADP > ␣,␤meATP (P 2X -selective), whereas the P 1 purinoceptor agonist adenosine was ineffective. The effect of ATP was suppressed by the poorly subtypeselective P 2 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 10 ؊9 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 [1-14 C]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 P 2 purinoceptors, possibly by a yet unknown subtype of the P 2Y purinoceptor family.It is well established that ATP acts as an extracellular signal in many tissues and is involved in a variety of regulatory processes including the control of vascular tone, muscle contraction, pain, or neuronal communication (for review see Ref.1). In particular, ATP serves as a neurotransmitter or cotransmitter in central, as well as in peripheral neurons (1, 2). For instance, ATP is co-released with noradrenaline or acetylcholine from sympathetic or parasympathetic nerve endings, respectively, and even from neuromuscular synapses (1). Another source of extracellular ATP is that released from parenchymal cells under hypoxic or ischemic conditions (3).Many biological responses to ATP are mediated via P 2 purinoceptors, which belong to either of two structurally and functionally distinct families of receptors: ligand-gated, nonselective cation channels (P 2X -type), or G-protein-coupled receptors linked to the phospholipase C...

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