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Ni²⁺ Block of Ca_V3.1 (1G) T-type Calcium Channels

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106

Correspondence to Stephen W. Jones: swj{at}case.edu

Ni²⁺ inhibits current through calcium channels, in part by blocking the pore, but Ni²⁺ may also allosterically affect channel activity via sites outside the permeation pathway. As a test for pore blockade, we examined whether the effect of Ni²⁺ on Ca_V3.1 is affected by permeant ions. We find two components to block by Ni²⁺, a rapid block with little voltage dependence, and a slow block most visible as accelerated tail currents. Rapid block is weaker for outward vs. inward currents (apparent K_d = 3 vs. 1 mM Ni²⁺, with 2 mM Ca²⁺ or Ba²⁺) and is reduced at high permeant ion concentration (110 vs. 2 mM Ca²⁺ or Ba²⁺). Slow block depends both on the concentration and on the identity of the permeant ion (Ca²⁺ vs. Ba²⁺ vs. Na⁺). Slow block is 2–3x faster in Ba²⁺ than in Ca²⁺ (2 or 110 mM), and is 10x faster with 2 vs. 110 mM Ca²⁺ or Ba²⁺. Slow block is orders of magnitude slower than the diffusion limit, except in the nominal absence of divalent cations (3 µM Ca²⁺). We conclude that both fast and slow block of Ca_V3.1 by Ni²⁺ are most consistent with occlusion of the pore. The exit rate of Ni²⁺ for slow block is reduced at high Ni²⁺ concentrations, suggesting that the site responsible for fast block can "lock in" slow block by Ni²⁺, at a site located deeper within the pore. In contrast to the complex pore block observed for Ca_V3.1, inhibition of Ca_V3.2 by Ni²⁺ was essentially independent of voltage, and was similar in 2 mM Ca²⁺ vs. Ba²⁺, consistent with inhibition by a different mechanism, at a site outside the pore.

© 2008 Obejero-Paz et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

				N. Khan, I. P. Gray, C. A. Obejero-Paz, and S. W. Jones Permeation and Gating in CaV3.1 ({alpha}1G) T-type Calcium Channels Effects of Ca2+, Ba2+, Mg2+, and Na+ J. Gen. Physiol., August 1, 2008; 132(2): 223 - 238. [Abstract] [Full Text] [PDF]

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