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

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 α1-subunit-dependent with lowest value for CaV1.2, and highest for CaV3.1; the sensitivity of the channels to Zn2+ was approximately ranked as CaV1.2 > CaV3.2 > CaV2.3 > CaV2.2 = CaV 2.1 ≥ CaV3.3 = CaV3.1. Although the CaV2.2 and CaV3.1 channels had similar IC50 for Zn2+ in Ba2+, the CaV2.2, but not CaV3.1 channels, had ∼10-fold higher IC50 to Zn2+ in Ca2+. The reduced sensitivity of CaV2.2 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 α1 pore regions. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of zinc on various Ca2+ channel subtypes.