Activation of a purinergic P2 receptor by adenosine 5'-triphosphate (ATP) has previously been shown to open a non-selective cation channel with a reversal potential of approximately 0 mV. We examined the effect of P2 receptor activation on voltage-gated ionic currents in acutely isolated CA3 pyramidal neurons from guinea pig hippocampus using the whole-cell-patch technique. Under conditions designed to isolate current through voltage-dependent Ca channels (ICa), ATP (50 microM) potentiated ICa by 36%. This increase in ICa desensitized back to control levels within 4 min. In contrast to the non-selective cation channel, ICa elicited from a holding potential (HP) of -100 mV showed significant potentiation in response to ATP when depolarized to a test potential (TP) of -10 mV but showed no effect on ICa when the same neuron was alternately depolarized to TP = -70 mV. No change in holding current at HP = -100 mV occurred. Tail currents were unaffected by ATP exposure suggesting that ICa potentiation was not due to modulation of L-type Ca channels. This potentiation was also observed either with ATP-gamma-s, the slowly hydrolyzable ATP analog, or with ATP in the presence of alpha, beta-methylene-ADP, an ectonucleotidase inhibitor, indicating that the effects observed were not due to activation of an adenosine receptor that required ATP hydrolysis. The potentiation of ICa was not observed with the P2X agonist, beta, gamma-methylene-ATP. These results suggest that ATP receptors can modulate voltage- as well as ligand-gated channels permeable to calcium and may play an important role in the dynamics of intracellular Ca2+ in these neurons.