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Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels
Ni(2+) inhibits current through calcium channels, in part by blocking the pore, but Ni(2+) may also allosterically affect channel activity via sites outside the permeation pathway. As a test for pore blockade, we examined whether the effect of Ni(2+) on Ca(V)3.1 is affected by permeant ions. We find...
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483332/ https://www.ncbi.nlm.nih.gov/pubmed/18663132 http://dx.doi.org/10.1085/jgp.200809988 |
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author | Obejero-Paz, Carlos A. Gray, I. Patrick Jones, Stephen W. |
author_facet | Obejero-Paz, Carlos A. Gray, I. Patrick Jones, Stephen W. |
author_sort | Obejero-Paz, Carlos A. |
collection | PubMed |
description | Ni(2+) inhibits current through calcium channels, in part by blocking the pore, but Ni(2+) may also allosterically affect channel activity via sites outside the permeation pathway. As a test for pore blockade, we examined whether the effect of Ni(2+) on Ca(V)3.1 is affected by permeant ions. We find two components to block by Ni(2+), 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 Ni(2+), with 2 mM Ca(2+) or Ba(2+)) and is reduced at high permeant ion concentration (110 vs. 2 mM Ca(2+) or Ba(2+)). Slow block depends both on the concentration and on the identity of the permeant ion (Ca(2+) vs. Ba(2+) vs. Na(+)). Slow block is 2–3× faster in Ba(2+) than in Ca(2+) (2 or 110 mM), and is ∼10× faster with 2 vs. 110 mM Ca(2+) or Ba(2+). Slow block is orders of magnitude slower than the diffusion limit, except in the nominal absence of divalent cations (∼3 μM Ca(2+)). We conclude that both fast and slow block of Ca(V)3.1 by Ni(2+) are most consistent with occlusion of the pore. The exit rate of Ni(2+) for slow block is reduced at high Ni(2+) concentrations, suggesting that the site responsible for fast block can “lock in” slow block by Ni(2+), at a site located deeper within the pore. In contrast to the complex pore block observed for Ca(V)3.1, inhibition of Ca(V)3.2 by Ni(2+) was essentially independent of voltage, and was similar in 2 mM Ca(2+) vs. Ba(2+), consistent with inhibition by a different mechanism, at a site outside the pore. |
format | Text |
id | pubmed-2483332 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-24833322009-02-01 Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels Obejero-Paz, Carlos A. Gray, I. Patrick Jones, Stephen W. J Gen Physiol Articles Ni(2+) inhibits current through calcium channels, in part by blocking the pore, but Ni(2+) may also allosterically affect channel activity via sites outside the permeation pathway. As a test for pore blockade, we examined whether the effect of Ni(2+) on Ca(V)3.1 is affected by permeant ions. We find two components to block by Ni(2+), 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 Ni(2+), with 2 mM Ca(2+) or Ba(2+)) and is reduced at high permeant ion concentration (110 vs. 2 mM Ca(2+) or Ba(2+)). Slow block depends both on the concentration and on the identity of the permeant ion (Ca(2+) vs. Ba(2+) vs. Na(+)). Slow block is 2–3× faster in Ba(2+) than in Ca(2+) (2 or 110 mM), and is ∼10× faster with 2 vs. 110 mM Ca(2+) or Ba(2+). Slow block is orders of magnitude slower than the diffusion limit, except in the nominal absence of divalent cations (∼3 μM Ca(2+)). We conclude that both fast and slow block of Ca(V)3.1 by Ni(2+) are most consistent with occlusion of the pore. The exit rate of Ni(2+) for slow block is reduced at high Ni(2+) concentrations, suggesting that the site responsible for fast block can “lock in” slow block by Ni(2+), at a site located deeper within the pore. In contrast to the complex pore block observed for Ca(V)3.1, inhibition of Ca(V)3.2 by Ni(2+) was essentially independent of voltage, and was similar in 2 mM Ca(2+) vs. Ba(2+), consistent with inhibition by a different mechanism, at a site outside the pore. The Rockefeller University Press 2008-08 /pmc/articles/PMC2483332/ /pubmed/18663132 http://dx.doi.org/10.1085/jgp.200809988 Text en © 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/). |
spellingShingle | Articles Obejero-Paz, Carlos A. Gray, I. Patrick Jones, Stephen W. Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels |
title | Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels |
title_full | Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels |
title_fullStr | Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels |
title_full_unstemmed | Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels |
title_short | Ni(2+) Block of Ca(V)3.1 (α1G) T-type Calcium Channels |
title_sort | ni(2+) block of ca(v)3.1 (α1g) t-type calcium channels |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483332/ https://www.ncbi.nlm.nih.gov/pubmed/18663132 http://dx.doi.org/10.1085/jgp.200809988 |
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