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 Cav3.1 (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 Cav3.1 channels (210 ± 20 pA at −60 mV with 2 mM Cd2+). Cav3.1 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 Cav3.1 channels.
Footnotes
This work was supported in part by the Deutsche Forschungsgemeinschaft [Grant TH345/11-1] and the Stiftung Westermann-Westdorp.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- ZIP
- Zrt- and Irt-like protein
- HBSS
- Hanks' balanced salt solution
- NMDG
- N-methyl-d-glucamine
- GHK
- Goldman-Hodgkin-Katz
- [Cd2+]o
- extracellular Cd2+ concentration
- NNC 55-0396
- (1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride.
- Received May 22, 2012.
- Accepted September 11, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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