MODULATION BY EXTRACELLULAR ATP OF 2 DISTINCT CURRENTS IN RAT MYOCYTES

The whole cell voltage-clamp technique was used to study the electroph ysiological effects induced by ATP in isolated ventricular myocytes. A TP or 2-methylthio-ATP evoked a transient inward current (I(ATP)) when the transmembrane potential (V(m)) was held at -70 mV and increased t he Ca2+ current (I(Ca)) when V(m) was depolarized to 0 mV. The time co urse of I(ATP) was fitted by a single exponential equation with a brie f time constant (165 ms), whereas the time course of enhancement of I( Ca) by ATP was also fitted by a single exponential equation with a muc h longer time constant (14 s). I(ATP) was much less pronounced when ex tracellular Mg2+ was absent, and it was insensitive to dihydropyridine s. In contrast, the enhancement of I(Ca) by ATP was not affected by re moving extracellular Mg2+, but it was suppressed by Ca2+ channel block ers. Both I(ATP) and I(Ca) were decreased by extracellular Cd2+. Inter nally applied guanosine 5'-O-(2-thiodiphosphate), which prevents the a ctivation of G proteins, abolished the ATP-enhanced rise in I(Ca) but did not inhibit I(ATP). These data suggest that ATP eliCitS I(ATP) and increases I(Ca) through two different mechanisms. I(ATP) appears to b e generated via receptor-operated channels that are activated by ATP. The ATP-induced increase of I(Ca) appears to be mediated by G proteins via pathways that are independent of adenosine 3',5'-cyclic monophosp hate and phosphoinositide turnover.