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  • Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study.

Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study.

The Journal of general physiology (2020-06-20)
Felix Neumaier, Serdar Alpdogan, Jürgen Hescheler, Toni Schneider
ABSTRACT

Loosely bound Zn2+ ions are increasingly recognized as potential modulators of synaptic plasticity and neuronal excitability under normal and pathophysiological conditions. Cav2.3 voltage-gated Ca2+ channels are among the most sensitive targets of Zn2+ and are therefore likely to be involved in the neuromodulatory actions of endogenous Zn2+. Although histidine residues on the external side of domain I have been implicated in the effects on Cav2.3 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 Zn2+-induced changes in Cav2.3 channel function. Our most important findings are that multiple high- and low-affinity mechanisms contribute to the net Zn2+ action, that Zn2+ can either inhibit or stimulate Ca2+ influx through Cav2.3 channels depending on resting membrane potential, and that Zn2+ effects may persist for some time even after cessation of the Zn2+ signal. Computer simulations show that (1) most salient features of Cav2.3 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 Zn2+ can be accounted for by assuming that Zn2+ binding to a first site is associated with an electrostatic modification and mechanical slowing of one of the voltage sensors, whereas Zn2+ 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 Zn2+ effects on Cav2.3 channel function and a step toward the application of computational approaches for predicting the complex actions of Zn2+ on neuronal excitability.

MATERIALS
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Cesium hydroxide solution, 50 wt. % in H2O, 99.9% trace metals basis
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Pyruvic acid, 98%
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