We examined the effect of zinc on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes as simple heteromers of alpha2, alpha3, or alpha4 and beta2 or beta4. Coapplication of zinc with low concentrations of acetylcholine (</=EC(10)) resulted in differential effects depending on receptor subunit composition. The alpha2beta2, alpha2beta4, alpha3beta4, alpha4beta2, and alpha4beta4 receptors exhibited biphasic modulation by zinc, with potentiation of the acetylcholine response occurring at 1-100 micrometer zinc and inhibition occurring at higher zinc concentrations. In contrast, alpha3beta2 receptors were only inhibited by zinc (IC(50) = 97 +/- 16 micrometer). The greatest potentiating effect of zinc was seen with alpha4beta4 receptors that were potentiated to 560 +/- 17% of the response to ACh alone, with an EC(50) of 22 +/- 4 micrometer zinc. Cadmium, but not nickel, was also able to potentiate alpha4beta4 receptors. Both zinc potentiation of alpha4beta4 receptors and zinc inhibition of alpha3beta2 receptors were voltage independent. The sensitivity of zinc potentiation of alpha4beta4 to diethylpyrocarbonate treatment and alterations in pH suggested the involvement of histidine residues. Zinc continued to inhibit alpha4beta4 and alpha3beta2 after diethylpyrocarbonate treatment. Application of a potentiating zinc concentration increased the response of alpha4beta2 and alpha4beta4 receptors to saturating ACh concentrations. The rate of Ach-induced desensitization of these receptors was unaffected by zinc. Our results reveal zinc potentiation as a new mode of neuronal nAChR modulation.