The ATP-activated inward current (IATP) in cultured rat superior cervical ganglion neurons and its modulation by extracellular Zn2+ were examined. ATP activated a non-specific cation conductance and caused a transient rise in intracellular Ca2+. The current response was specifically activated by ATP and was blocked by the P2-purinoceptor antagonist, suramin. Low concentrations of extracellular Zn2+ rapidly and reversibly potentiated both IATP and the intracellular Ca2+ rise. The potentiation by 10 microM Zn2+ was dependent on the concentration of agonist; Zn2+ increased the sensitivity of activation without potentiating the maximum response. Higher concentrations of Zn2+ reduced and prolonged the current, consistent with open-channel block. We hypothesize that there exist two sites of action for Zn2+: a positively acting allosteric site that enhances current amplitude and a site, possibly within the pore, that blocks conductance through the channel.