Differential modulation by copper and zinc of P2X2 and P2X4 receptor function

The modulation by CU2+ and Zn2+ of P2X(2) and P2X(4) receptors expressed in Xenopus oocytes was studied with the two-electrode, voltage-clamp technique. In oocytes expressing P2X(2) receptors, both CU2+ and Zn2+ in the concentration range 1-130 mu M, reversibly potentiated current activated by submaximal concentrations of ATP. The CU2+,and Zn2+ concentrations that produced 50% of maximal potentiation (EC50) of current activated by 50 mu M ATP were 16.3 If: 0.9 (SE) ELM and 19.6 +/- 1.5 mu M, respectively. CU2+,and Zn2+ potentiation of ATP-activated current was independent of membrane potential between -80 and +20 mV and did not involve a shift in the reversal potential of the current. Like Zn2+, CU2+ increased the apparent affinity of the receptor for ATP, as evidenced by a parallel shift of the ATP concentration-response curve to the left. However, CU2+ did not enhance ATP-activated current in the presence of a;maximally effective concentration of Zn2+, suggesting a common site or mechanism of action of CU2+ and Zn2+ on P2X(2) receptors. For the P2X(4) receptor, Zn2+, from 0.5 to 20 mu M enhanced current activated by 5 mu M ATP with an EC50 value of 2.4 +/- 0.2 mu M. Zn2+ Shifted the ATP concentration-response curve to the left in a parallel manner, and potentiation by Zn2+ was voltage independent. By contrast, CU2+ in a similar concentration range did not affect ATP-activated current in oocytes expressing P2X(4), receptors, and CU2+ did not alter the potentiation of ATP-activated current produced by Zn2+. The results su,suggest that CU2+ and Zn2+,zi differentially modulate the function of P2X(2), and P2X(4), receptors, perhaps because of differences in a shared site of action on both subunits or the absence of a site for Cu2+ action on the P2X(4), receptor.