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Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling

Adenosine triphosphate (ATP)-gated P2X2 receptors exhibit two opposite activation-dependent changes, pore dilation and pore closing (desensitization), through a process that is incompletely understood. To address this issue and to clarify the roles of calcium and the C-terminal domain in gating, we...

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Autores principales: Khadra, Anmar, Yan, Zonghe, Coddou, Claudio, Tomić, Melanija, Sherman, Arthur, Stojilkovic, Stanko S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343373/
https://www.ncbi.nlm.nih.gov/pubmed/22547664
http://dx.doi.org/10.1085/jgp.201110716
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author Khadra, Anmar
Yan, Zonghe
Coddou, Claudio
Tomić, Melanija
Sherman, Arthur
Stojilkovic, Stanko S.
author_facet Khadra, Anmar
Yan, Zonghe
Coddou, Claudio
Tomić, Melanija
Sherman, Arthur
Stojilkovic, Stanko S.
author_sort Khadra, Anmar
collection PubMed
description Adenosine triphosphate (ATP)-gated P2X2 receptors exhibit two opposite activation-dependent changes, pore dilation and pore closing (desensitization), through a process that is incompletely understood. To address this issue and to clarify the roles of calcium and the C-terminal domain in gating, we combined biophysical and mathematical approaches using two splice forms of receptors: the full-size form (P2X2aR) and the shorter form missing 69 residues in the C-terminal domain (P2X2bR). Both receptors developed conductivity for N-methyl-d-glucamine within 2–6 s of ATP application. However, pore dilation was accompanied with a decrease rather than an increase in the total conductance, which temporally coincided with rapid and partial desensitization. During sustained agonist application, receptors continued to desensitize in calcium-independent and calcium-dependent modes. Calcium-independent desensitization was more pronounced in P2X2bR, and calcium-dependent desensitization was more pronounced in P2X2aR. In whole cell recording, we also observed use-dependent facilitation of desensitization of both receptors. Such behavior was accounted for by a 16-state Markov kinetic model describing ATP binding/unbinding and activation/desensitization. The model assumes that naive receptors open when two to three ATP molecules bind and undergo calcium-independent desensitization, causing a decrease in the total conductance, or pore dilation, causing a shift in the reversal potential. In calcium-containing media, receptor desensitization is facilitated and the use-dependent desensitization can be modeled by a calcium-dependent toggle switch. The experiments and the model together provide a rationale for the lack of sustained current growth in dilating P2X2Rs and show that receptors in the dilated state can also desensitize in the presence of calcium.
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spelling pubmed-33433732012-11-01 Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling Khadra, Anmar Yan, Zonghe Coddou, Claudio Tomić, Melanija Sherman, Arthur Stojilkovic, Stanko S. J Gen Physiol Article Adenosine triphosphate (ATP)-gated P2X2 receptors exhibit two opposite activation-dependent changes, pore dilation and pore closing (desensitization), through a process that is incompletely understood. To address this issue and to clarify the roles of calcium and the C-terminal domain in gating, we combined biophysical and mathematical approaches using two splice forms of receptors: the full-size form (P2X2aR) and the shorter form missing 69 residues in the C-terminal domain (P2X2bR). Both receptors developed conductivity for N-methyl-d-glucamine within 2–6 s of ATP application. However, pore dilation was accompanied with a decrease rather than an increase in the total conductance, which temporally coincided with rapid and partial desensitization. During sustained agonist application, receptors continued to desensitize in calcium-independent and calcium-dependent modes. Calcium-independent desensitization was more pronounced in P2X2bR, and calcium-dependent desensitization was more pronounced in P2X2aR. In whole cell recording, we also observed use-dependent facilitation of desensitization of both receptors. Such behavior was accounted for by a 16-state Markov kinetic model describing ATP binding/unbinding and activation/desensitization. The model assumes that naive receptors open when two to three ATP molecules bind and undergo calcium-independent desensitization, causing a decrease in the total conductance, or pore dilation, causing a shift in the reversal potential. In calcium-containing media, receptor desensitization is facilitated and the use-dependent desensitization can be modeled by a calcium-dependent toggle switch. The experiments and the model together provide a rationale for the lack of sustained current growth in dilating P2X2Rs and show that receptors in the dilated state can also desensitize in the presence of calcium. The Rockefeller University Press 2012-05 /pmc/articles/PMC3343373/ /pubmed/22547664 http://dx.doi.org/10.1085/jgp.201110716 Text en © 2012 Khadra 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.rupress.org/terms). 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 Article
Khadra, Anmar
Yan, Zonghe
Coddou, Claudio
Tomić, Melanija
Sherman, Arthur
Stojilkovic, Stanko S.
Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling
title Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling
title_full Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling
title_fullStr Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling
title_full_unstemmed Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling
title_short Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling
title_sort gating properties of the p2x2a and p2x2b receptor channels: experiments and mathematical modeling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343373/
https://www.ncbi.nlm.nih.gov/pubmed/22547664
http://dx.doi.org/10.1085/jgp.201110716
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