Extracellular Zn 2+ modulates current passage through voltage- and neurotransmitter-gated ion channels, at concentrations less than, or near, those produced by release at certain synapses. Electrophysiological effects of cytoplasmic Zn 2+ are less well understood, and effects have been observed at concentrations that are orders of magnitude greater than those found in resting and stimulated neurons. To examine whether and how neurons are affected by lower levels of cytoplasmic Zn 2+, we tested the effect of Zn 2+-selective chelators, Zn 2+-preferring ionophores, and exogenous Zn 2+ on neuronal somata during whole-cell patch-clamp recordings. We report here that cytoplasmic zinc facilitates the downward regulation of a background Cl − conductance by an endogenous protein kinase C (PKC) in fish retinal ganglion cell somata and that this regulation is maintained if nanomolar levels of free Zn 2+ are available. This regulation has not been described previously in any tissue, as other Cl − currents have been described as reduced by PKC alone, reduced by Zn 2+ alone, or reduced by both independently. Moreover, control of cation currents by a zinc-dependent PKC has not been reported previously. The regulation we have observed thus provides the first electrophysiological measurements consistent with biochemical measurements of zinc-dependent PKC activity in other systems. These results suggest that contributions of background Cl − conductances to electrical properties of neurons are susceptible to modulation.