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Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant
Serotonin (5-HT) plays a central role in various brain functions via the activation of a family of receptors, most of them G protein coupled receptors (GPCRs). 5-HT(1A) receptor, the most abundant 5-HT receptors, was implicated in many brain dysfunctions and is a major target for drug discovery. Sev...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547147/ https://www.ncbi.nlm.nih.gov/pubmed/37795037 http://dx.doi.org/10.3389/fphar.2023.1270726 |
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author | Tauber, Merav Ben-Chaim, Yair |
author_facet | Tauber, Merav Ben-Chaim, Yair |
author_sort | Tauber, Merav |
collection | PubMed |
description | Serotonin (5-HT) plays a central role in various brain functions via the activation of a family of receptors, most of them G protein coupled receptors (GPCRs). 5-HT(1A) receptor, the most abundant 5-HT receptors, was implicated in many brain dysfunctions and is a major target for drug discovery. Several genetic polymorphisms within the 5-HT(1A) receptor gene were identified and linked to different conditions, including anxiety and depression. Here, we used Xenopus oocytes to examine the effects of one of the functional polymorphism, Arg220Leu, on the function of the receptor. We found that the mutated receptor shows normal activation of G protein and normal 5-HT binding. On the other hand, the mutated receptor shows impaired desensitization, probably due to impairment in activation of β arrestin-dependent pathway. Furthermore, while the 5-HT(1A) receptor was shown to exhibit voltage dependent activation by serotonin and by buspirone, the mutated receptor was voltage-independent. Our results suggest a pronounced effect of the mutation on the function of the 5-HT(1A) receptor and add to our understanding of the molecular mechanism of its voltage dependence. Moreover, the findings of this study may suggest a functional explanation for the possible link between this variant and brain pathologies. |
format | Online Article Text |
id | pubmed-10547147 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105471472023-10-04 Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant Tauber, Merav Ben-Chaim, Yair Front Pharmacol Pharmacology Serotonin (5-HT) plays a central role in various brain functions via the activation of a family of receptors, most of them G protein coupled receptors (GPCRs). 5-HT(1A) receptor, the most abundant 5-HT receptors, was implicated in many brain dysfunctions and is a major target for drug discovery. Several genetic polymorphisms within the 5-HT(1A) receptor gene were identified and linked to different conditions, including anxiety and depression. Here, we used Xenopus oocytes to examine the effects of one of the functional polymorphism, Arg220Leu, on the function of the receptor. We found that the mutated receptor shows normal activation of G protein and normal 5-HT binding. On the other hand, the mutated receptor shows impaired desensitization, probably due to impairment in activation of β arrestin-dependent pathway. Furthermore, while the 5-HT(1A) receptor was shown to exhibit voltage dependent activation by serotonin and by buspirone, the mutated receptor was voltage-independent. Our results suggest a pronounced effect of the mutation on the function of the 5-HT(1A) receptor and add to our understanding of the molecular mechanism of its voltage dependence. Moreover, the findings of this study may suggest a functional explanation for the possible link between this variant and brain pathologies. Frontiers Media S.A. 2023-09-18 /pmc/articles/PMC10547147/ /pubmed/37795037 http://dx.doi.org/10.3389/fphar.2023.1270726 Text en Copyright © 2023 Tauber and Ben-Chaim. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Tauber, Merav Ben-Chaim, Yair Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant |
title | Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant |
title_full | Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant |
title_fullStr | Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant |
title_full_unstemmed | Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant |
title_short | Functional consequences of a rare human serotonergic 5-HT(1A) receptor variant |
title_sort | functional consequences of a rare human serotonergic 5-ht(1a) receptor variant |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547147/ https://www.ncbi.nlm.nih.gov/pubmed/37795037 http://dx.doi.org/10.3389/fphar.2023.1270726 |
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