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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The Rockefeller University Press
2012
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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. |
format | Online Article Text |
id | pubmed-3343373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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