EXTRACELLULAR ATP ACTIVATES COORDINATED NA+, PI, AND CA2+ TRANSPORT IN CARDIAC MYOCYTES

Activation of an ATP receptor has previously been shown to induce cytosolic [Ca2+] transients in rat ventricular myocytes. A slower but larger [Ca2+] increase which can cause cell hypercontraction follows the transient when extracellular P(i) is increased. This second phase of the [Ca2+] response is stimulated by ATP or adenosine 5'-(gamma-thio)triphosphate in a medium containing 11.2 mM P(i), but not by high concentrations of 2-methylthio-ATP, which stimulate only the initial [Ca2+] transient. Replacing medium Na+ with N-methyl-D-glucamine suppresses this P(i)-dependent [Ca2+] increase following ATP addition, suggesting a causal relationship between Na+ transport and Ca2+ influx. Blocking voltage-sensitive Na+ channels, Na+-H+ exchange, or Na+-K+-Cl- cotransport did not reduce ATP-induced cell hypercontraction in 11.2 mM P(i) medium, suggesting that these transporters are not involved. ATP stimulation of Na+-P(i) cotransport was investigated with isotopic methods. The results were consistent with the hypothesis that extracellular ATP stimulates Na+-P(i) cotransport, which activates Na+-Ca2+ exchange. A novel P(i)-dependent ATP receptor-effector system has been demonstrated in cardiac cells, and it may have significant effects on cellular transport, contractility, and bioenergetics.