Differential zinc permeation and blockade of L-type Ca<SUP>2+</SUP> channel isoforms Cav1.2 and Cav1.3

초록

Certain voltage-activated Ca2+ channels have been reported to act as potential zinc entry routes. However, it remains to be determined whether zinc can permeate individual Ca2+ channel isoforms. We expressed recombinant Ca2+ channel isoforms in Xenopus oocytes and attempted to record zinc currents from them using a two-electrode voltage clamp method. We found that, in an extracellular zinc solution, inward currents arising from zinc permeation could be recorded from Xenopus oocytes expressing L-type Ca(v)1.2 or Ca(v)1.3 isoforms, but not from oocytes expressing Ca(v)22, Ca(v)23, Ca(v)3.1, or Ca(v)3.2. Zinc currents through Ca(v)1.2 and Ca(v)13 were blocked by nimodipine, but enhanced by (+/-)Bay K8644, supporting the finding that zinc can permeate both L-type Ca(v)1.2 and Ca(v)13 channel isoforms. We also examined the blocking effects of low concentrations of zinc on Ca2+ currents through the L-type channel isoforms. Low micro-molar zinc potently blocked Ca2+ currents through Ca(v)1.2 and Ca(v)1.3 with different sensitivities (IC50 for Ca(v)1.2 and Ca(v)1.3 = 18.4 and 34.1 mu M) and de-accelerated the activation and inactivation kinetics in a concentration-dependent manner. Notably, mild acidifications of the external zinc solution increased zinc currents through Ca(v)12 and Ca(v)1.3, with the increment level for Ca(v)13 being greater than that for Ca(v)1.2. In overall, we provide evidence that Ca(v)1.2 and Ca(v)1.3 isoforms are capable of potentially functioning as zinc permeation routes, through which zinc entry can be differentially augmented by mild acidifications. (C) 2015 Elsevier B.V. All rights reserved.

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