Inhibition of the Glycine Receptor alpha 3 Function by Colchicine
Colchicine is a plant alkaloid that is widely used as a therapeutic agent. It is widely accepted that colchicine reduces the production of inflammatory mediators mainly by altering cytoskeleton dynamics due to its microtubule polymerization inhibitory activity. However, other lines of evidence have...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.01143/full |
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| author | Carola Muñoz-Montesino Carlos F. Burgos Cesar O. Lara Camila R. Riquelme David Flaig Victoria P. San Martin Luis G. Aguayo Jorge Fuentealba Patricio A. Castro Leonardo Guzmán Gonzalo E. Yévenes Gustavo Moraga-Cid |
| author_facet | Carola Muñoz-Montesino Carlos F. Burgos Cesar O. Lara Camila R. Riquelme David Flaig Victoria P. San Martin Luis G. Aguayo Jorge Fuentealba Patricio A. Castro Leonardo Guzmán Gonzalo E. Yévenes Gustavo Moraga-Cid |
| author_sort | Carola Muñoz-Montesino |
| collection | DOAJ |
| description | Colchicine is a plant alkaloid that is widely used as a therapeutic agent. It is widely accepted that colchicine reduces the production of inflammatory mediators mainly by altering cytoskeleton dynamics due to its microtubule polymerization inhibitory activity. However, other lines of evidence have shown that colchicine exerts direct actions on the function of ion channels, which are independent of cytoskeleton alterations. Colchicine is able to modify the function of several pentameric ligand-gated ion channels, including glycine receptors (GlyRs). Previous electrophysiological studies have shown that colchicine act as an antagonist of GlyRs composed by the α1 subunit. In addition, it was recently demonstrated that colchicine directly bind to the α3 subunit of GlyRs. Interestingly, other studies have shown a main role of α3GlyRs on chronic inflammatory pain. Nevertheless, the functional effects of colchicine on the α3GlyR function are still unknown. Here, by using electrophysiological techniques and bioinformatics, we show that colchicine inhibited the function of the α3GlyRs. Colchicine elicited concentration-dependent inhibitory effects on α3GlyRs at micromolar range and decreased the apparent affinity for glycine. Single-channel recordings show that the colchicine inhibition is associated with a decrease in the open probability of the ion channel. Molecular docking assays suggest that colchicine preferentially bind to the orthosteric site in the closed state of the ion channel. Altogether, our results suggest that colchicine is a competitive antagonist of the α3GlyRs. |
| first_indexed | 2024-12-24T05:23:34Z |
| format | Article |
| id | doaj.art-cf4bb000006546e88ab343779698826c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-24T05:23:34Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-cf4bb000006546e88ab343779698826c2022-12-21T17:13:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-07-011110.3389/fphar.2020.01143515955Inhibition of the Glycine Receptor alpha 3 Function by ColchicineCarola Muñoz-MontesinoCarlos F. BurgosCesar O. LaraCamila R. RiquelmeDavid FlaigVictoria P. San MartinLuis G. AguayoJorge FuentealbaPatricio A. CastroLeonardo GuzmánGonzalo E. YévenesGustavo Moraga-CidColchicine is a plant alkaloid that is widely used as a therapeutic agent. It is widely accepted that colchicine reduces the production of inflammatory mediators mainly by altering cytoskeleton dynamics due to its microtubule polymerization inhibitory activity. However, other lines of evidence have shown that colchicine exerts direct actions on the function of ion channels, which are independent of cytoskeleton alterations. Colchicine is able to modify the function of several pentameric ligand-gated ion channels, including glycine receptors (GlyRs). Previous electrophysiological studies have shown that colchicine act as an antagonist of GlyRs composed by the α1 subunit. In addition, it was recently demonstrated that colchicine directly bind to the α3 subunit of GlyRs. Interestingly, other studies have shown a main role of α3GlyRs on chronic inflammatory pain. Nevertheless, the functional effects of colchicine on the α3GlyR function are still unknown. Here, by using electrophysiological techniques and bioinformatics, we show that colchicine inhibited the function of the α3GlyRs. Colchicine elicited concentration-dependent inhibitory effects on α3GlyRs at micromolar range and decreased the apparent affinity for glycine. Single-channel recordings show that the colchicine inhibition is associated with a decrease in the open probability of the ion channel. Molecular docking assays suggest that colchicine preferentially bind to the orthosteric site in the closed state of the ion channel. Altogether, our results suggest that colchicine is a competitive antagonist of the α3GlyRs.https://www.frontiersin.org/article/10.3389/fphar.2020.01143/fullglycine receptorantagonistcolchicinepentameric ligand-gated ion channelpain |
| spellingShingle | Carola Muñoz-Montesino Carlos F. Burgos Cesar O. Lara Camila R. Riquelme David Flaig Victoria P. San Martin Luis G. Aguayo Jorge Fuentealba Patricio A. Castro Leonardo Guzmán Gonzalo E. Yévenes Gustavo Moraga-Cid Inhibition of the Glycine Receptor alpha 3 Function by Colchicine Frontiers in Pharmacology glycine receptor antagonist colchicine pentameric ligand-gated ion channel pain |
| title | Inhibition of the Glycine Receptor alpha 3 Function by Colchicine |
| title_full | Inhibition of the Glycine Receptor alpha 3 Function by Colchicine |
| title_fullStr | Inhibition of the Glycine Receptor alpha 3 Function by Colchicine |
| title_full_unstemmed | Inhibition of the Glycine Receptor alpha 3 Function by Colchicine |
| title_short | Inhibition of the Glycine Receptor alpha 3 Function by Colchicine |
| title_sort | inhibition of the glycine receptor alpha 3 function by colchicine |
| topic | glycine receptor antagonist colchicine pentameric ligand-gated ion channel pain |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.01143/full |
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