Zn(2+)-induced changes in Ca(v)2.3 channel function: An electrophysiological and modeling study

Loosely bound Zn(2+) ions are increasingly recognized as potential modulators of synaptic plasticity and neuronal excitability under normal and pathophysiological conditions. Ca(v)2.3 voltage-gated Ca(2+) channels are among the most sensitive targets of Zn(2+) and are therefore likely to be involved in the neuromodulatory actions of endogenous Zn(2+). Although histidine residues on the external side of domain I have been implicated in the effects on Ca(v)2.3 channel gating, the exact mechanisms involved in channel modulation remain incompletely understood. Here, we use a combination of electrophysiological recordings, modification of histidine residues, and computational modeling to analyze Zn(2+)-induced changes in Ca(v)2.3 channel function. Our most important findings are that multiple high- and low-affinity mechanisms contribute to the net Zn(2+) action, that Zn(2+) can either inhibit or stimulate Ca(2+) influx through Ca(v)2.3 channels depending on resting membrane potential, and that Zn(2+) effects may persist for some time even after cessation of the Zn(2+) signal. Computer simulations show that (1) most salient features of Ca(v)2.3 channel gating in the absence of trace metals can be reproduced by an obligatory model in which activation of two voltage sensors is necessary to open the pore; and (2) most, but not all, of the effects of Zn(2+) can be accounted for by assuming that Zn(2+) binding to a first site is associated with an electrostatic modification and mechanical slowing of one of the voltage sensors, whereas Zn(2+) binding to a second, lower-affinity site blocks the channel and modifies the opening and closing transitions. While still far from complete, our model provides a first quantitative framework for understanding Zn(2+) effects on Ca(v)2.3 channel function and a step toward the application of computational approaches for predicting the complex actions of Zn(2+) on neuronal excitability.