Abstract
The essential cation zinc (Zn 2+) blocks voltage-dependent calcium channels in several cell types, which exhibit different sensitivities to Zn 2+. The specificity of the Zn 2+ 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 Zn 2+ effect on low- and high-voltage activated channels. We found that in Ba 2+, the IC 50 value of Zn 2+ was α 1-subunit-dependent with lowest value for Ca V1.2, and highest for Ca V3.1; the sensitivity of the channels to Zn 2+ 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 IC 50 for Zn 2+ in Ba 2+, the Ca V2.2, but not Ca V3.1 channels, had ∼10-fold higher IC 50 to Zn 2+ in Ca 2+. The reduced sensitivity of Ca V2.2 channels to Zn 2+ in Ca 2+ 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 Zn 2+ block, mediated by multiple mechanisms, may depend on conformational changes surrounding the α 1 pore regions. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of zinc on various Ca 2+ channel subtypes.
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