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Zn²⁺ Sensitivity of High- and Low-Voltage Activated Calcium Channels

Department of Physiology, University of Toronto, Toronto, Ontario, Canada

Correspondence: Address reprint requests to Zhong-Ping Feng, Dept. of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. Tel.: 416-946-5506; Fax: 416-978-4940; E-mail: zp.feng{at}utoronto.ca.

The essential cation zinc (Zn²⁺) blocks voltage-dependent calcium channels in several cell types, which exhibit different sensitivities to Zn²⁺. The specificity of the Zn²⁺ effect on voltage-dependent calcium channel subtypes has not been systematically investigated. In this study, we used a transient protein expression system to determine the Zn²⁺ effect on low- and high-voltage activated channels. We found that in Ba²⁺, the IC₅₀ value of Zn²⁺ was ₁-subunit-dependent with lowest value for Ca_V1.2, and highest for Ca_V3.1; the sensitivity of the channels to Zn²⁺ was approximately ranked as Ca_V1.2 > Ca_V3.2 > Ca_V2.3 > Ca_V2.2 = Ca_V 2.1 Ca_V3.3 = Ca_V3.1. Although the Ca_V2.2 and Ca_V3.1 channels had similar IC₅₀ for Zn²⁺ in Ba²⁺, the Ca_V2.2, but not Ca_V3.1 channels, had 10-fold higher IC₅₀ to Zn²⁺ in Ca²⁺. The reduced sensitivity of Ca_V2.2 channels to Zn²⁺ in Ca²⁺ was partially reversed by disrupting a putative EF-hand motif located external to the selectivity filter EEEE locus. Thus, our findings support the notion that the Zn²⁺ block, mediated by multiple mechanisms, may depend on conformational changes surrounding the ₁ pore regions. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of zinc on various Ca²⁺ channel subtypes.