Whole-cell patch-clamp and fast perfusion were used to study the effects of zinc on adenosine 5'-triphosphate (ATP)-induced responses of histaminergic neurons. 2. At 10-30 micro M ATP, Zn(2+) had biphasic effects on ATP responses. Zn(2+) at 3-100 micro M increased the ATP-induced currents, but inhibited them at higher concentrations. 3. At 300 micro M ATP, Zn(2+) predominantly but incompletely inhibited the currents. 4. At 5 and 50 micro M, Zn(2+) shifted to the left the concentration-response curve for ATP-induced currents, without changing the maximal response. At 1 mM, Zn(2+) inhibited ATP-induced currents in a noncompetitive way, reducing the maximal response by 58%. .Zn(2+) increased the decay time of ATP-evoked currents nine fold with an EC(50) of 63 micro M. Upon removal of high concentrations of Zn(2+), there was a rapid increase of the current followed by a slow decline towards the response amplitude seen with ATP alone. The appearance of a tail current is consistent with a Zn(2+)-induced increase of ATP affinity and an inhibition of its efficacy. 6. Thus, Zn(2+) acts as a bidirectional modulator of ATP receptor channels in tuberomamillary neurons, which possess functional P2X(2) receptors. The data are consistent with the existence of two distinct modulatory sites on the P2X receptor, which can be occupied by Zn(2+). 7. Our data suggest that zinc-induced potentiation of ATP-mediated currents is caused by the slowing of ATP dissociation from the receptor, while inhibition of ATP-induced currents is related to the suppression of ATP receptor gating.
