Mercuric chloride exerted a biphasic modulatory effect on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes as heteromers of the alpha3 or alpha4 and beta2 or beta4 subunits. The degree of modulation was subunit-dependent, with beta4-containing receptors displaying greater potentiation and alpha4-containing receptors displaying greater inhibition. Thus, alpha4beta4 receptors displayed both robust potentiation and robust inhibition. During prolonged coapplication of HgCl(2), first potentiation then inhibition of the acetylcholine (ACh) response was observed. Upon coapplication of 1 microM HgCl(2), a 2-fold increase in ACh-induced current was achieved in 55 +/- 1 s. With continued HgCl(2) application, the ACh response was slowly inhibited until, after 5 min, less than 10% of the initial response remained. By measuring potentiation at its peak and inhibition 5 min after the start of HgCl(2) coapplication, we obtained EC(50) and IC(50) values of 262 +/- 75 and 430 +/- 72 nM, respectively. HgCl(2) potentiation was voltage-dependent, increasing at more positive holding potentials. Upon washout of mercury chloride, potentiation reversed with a t(1/2) of 4.6 min. Inhibition reversed more slowly, with less than half the initial response recovered after 15 min of wash. Although free cysteine residues are common targets for mercury, elimination of all free cysteines located in the extracellular domains of the alpha4 and beta4 subunits did not alter the effects of mercuric chloride. Potentiation and inhibition of neuronal nAChRs may occur through action at a transmembrane or cytoplasmic location after passive diffusion of mercuric chloride across the plasma membrane.