Several lines of evidence suggest a physiological role for Cu2+ in regulating nervous system function. In the present study using whole-cell patch-clamp recording, Cu2+ greatly enhanced current activated by 10 microM ATP in the majority of rat nodose ganglion neurons. The enhancement was concentration-dependent between 1 and 50 microM Cu2+, and had an EC50 of 6.1 microM. Cu2+ shifted the ATP concentration-response curve to the left in a parallel manner. However, Cu2+ did not enhance ATP-activated current in the presence of a maximally-effective concentration of Zn2+. The observations suggest that Cu2+ increases the affinity of the receptor for ATP by acting at the Zn2+ modulatory site. In addition, a subset of neurons in the nodose ganglion express ATP-gated receptor-channels that are insensitive to modulation by physiological concentrations of Cu2+, Zn2+ and protons.