Cd2+ Block and Permeation of CaV3.1 (α1G) T-Type Calcium Channels: Candidate Mechanism for Cd2+ Influx

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 (alpha 1G) 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, similar to 1%), which makes them a candidate pathway for Cd2+ entry into cells during Cd2+ exposure. Incubation with radiolabeled Cd-109(2+) confirmed uptake of Cd2+ into cells with Ca(v)3.1 channels.