Cd²⁺ block and permeation of CaV3.1 (α1G) T-type calcium channels: candidate mechanism for Cd²⁺ influx

Mol Pharmacol. 2012 Dec;82(6):1183-93. doi: 10.1124/mol.112.080176. Epub 2012 Sep 12.

Abstract

Cd²⁺ is an industrial pollutant that can cause cytotoxicity in multiple organs. We examined the effects of extracellular Cd²⁺ on permeation and gating of Ca(v)3.1 (α1G) channels stably transfected in HEK293 cells, by using whole-cell recording. With the use of instantaneous I-V currents (measured after strong depolarization) to isolate the effects on permeation, Cd²⁺ rapidly blocked currents with 2 mM Ca²⁺ in a voltage-dependent manner. The block caused by Cd²⁺ was relieved at more-hyperpolarized potentials, which suggests that Cd²⁺ can permeate through the selectivity filter of the channel into the cytosol. In the absence of other permeant ions (Ca²⁺ and Na⁺ replaced by N-methyl-d-glucamine), Cd²⁺ carried sizable inward currents through Ca(v)3.1 channels (210 ± 20 pA at -60 mV with 2 mM Cd²⁺). Ca(v)3.1 channels have a significant "window current" at that voltage (open probability, ∼1%), which makes them a candidate pathway for Cd²⁺ entry into cells during Cd²⁺ exposure. Incubation with radiolabeled ¹⁰⁹Cd²⁺ confirmed uptake of Cd²⁺ into cells with Ca(v)3.1 channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadmium / metabolism*
  • Cadmium / pharmacology*
  • Calcium / metabolism
  • Calcium Channels, T-Type / metabolism*
  • Cell Line
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects
  • Membrane Potentials / drug effects
  • Patch-Clamp Techniques / methods

Substances

  • CACNA1G protein, human
  • Calcium Channels, T-Type
  • Cadmium
  • Calcium