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GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner
G protein-coupled receptor 54 (GPR54) is a G(q/11)-coupled 7 transmembrane-spanning receptor (7TMR). Activation of GPR54 by kisspeptin (Kp) stimulates PIP(2) hydrolysis, Ca(2+) mobilization and ERK1/2 MAPK phosphorylation. Kp and GPR54 are established regulators of the hypothalamic-pituitary-gonadal...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944883/ https://www.ncbi.nlm.nih.gov/pubmed/20886089 http://dx.doi.org/10.1371/journal.pone.0012964 |
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author | Szereszewski, Jacob M. Pampillo, Macarena Ahow, Maryse R. Offermanns, Stefan Bhattacharya, Moshmi Babwah, Andy V. |
author_facet | Szereszewski, Jacob M. Pampillo, Macarena Ahow, Maryse R. Offermanns, Stefan Bhattacharya, Moshmi Babwah, Andy V. |
author_sort | Szereszewski, Jacob M. |
collection | PubMed |
description | G protein-coupled receptor 54 (GPR54) is a G(q/11)-coupled 7 transmembrane-spanning receptor (7TMR). Activation of GPR54 by kisspeptin (Kp) stimulates PIP(2) hydrolysis, Ca(2+) mobilization and ERK1/2 MAPK phosphorylation. Kp and GPR54 are established regulators of the hypothalamic-pituitary-gonadal (HPG) axis and loss-of-function mutations in GPR54 are associated with an absence of puberty and hypogonadotropic hypogonadism, thus defining an important role of the Kp/GPR54 signaling system in reproductive function. Given the tremendous physiological and clinical importance of the Kp/GPR54 signaling system, we explored the contributions of the GPR54-coupled G(q/11) and β-arrestin pathways on the activation of a major downstream signaling molecule, ERK, using G(q/11) and β-arrestin knockout mouse embryonic fibroblasts. Our study revealed that GPR54 employs the G(q/11) and β-arrestin-2 pathways in a co-dependent and temporally overlapping manner to positively regulate ERK activity and pERK nuclear localization. We also show that while β-arrestin-2 potentiates GPR54 signaling to ERK, β-arrestin-1 inhibits it. Our data also revealed that diminished β-arrestin-1 and -2 expression in the GT1-7 GnRH hypothalamic neuronal cell line triggered distinct patterns of gene expression following Kp-10 treatment. Thus, β-arrestin-1 and -2 also regulate distinct downstream responses in gene expression. Finally, we showed that GPR54, when uncoupled from the G(q/11) pathway, as is the case for several naturally occurring GPR54 mutants associated with hypogonadotropic hypogonadism, continues to regulate gene expression in a G protein-independent manner. These new and exciting findings add significantly to our mechanistic understanding of how this important receptor signals intracellularly in response to kisspeptin stimulation. |
format | Text |
id | pubmed-2944883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29448832010-09-30 GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner Szereszewski, Jacob M. Pampillo, Macarena Ahow, Maryse R. Offermanns, Stefan Bhattacharya, Moshmi Babwah, Andy V. PLoS One Research Article G protein-coupled receptor 54 (GPR54) is a G(q/11)-coupled 7 transmembrane-spanning receptor (7TMR). Activation of GPR54 by kisspeptin (Kp) stimulates PIP(2) hydrolysis, Ca(2+) mobilization and ERK1/2 MAPK phosphorylation. Kp and GPR54 are established regulators of the hypothalamic-pituitary-gonadal (HPG) axis and loss-of-function mutations in GPR54 are associated with an absence of puberty and hypogonadotropic hypogonadism, thus defining an important role of the Kp/GPR54 signaling system in reproductive function. Given the tremendous physiological and clinical importance of the Kp/GPR54 signaling system, we explored the contributions of the GPR54-coupled G(q/11) and β-arrestin pathways on the activation of a major downstream signaling molecule, ERK, using G(q/11) and β-arrestin knockout mouse embryonic fibroblasts. Our study revealed that GPR54 employs the G(q/11) and β-arrestin-2 pathways in a co-dependent and temporally overlapping manner to positively regulate ERK activity and pERK nuclear localization. We also show that while β-arrestin-2 potentiates GPR54 signaling to ERK, β-arrestin-1 inhibits it. Our data also revealed that diminished β-arrestin-1 and -2 expression in the GT1-7 GnRH hypothalamic neuronal cell line triggered distinct patterns of gene expression following Kp-10 treatment. Thus, β-arrestin-1 and -2 also regulate distinct downstream responses in gene expression. Finally, we showed that GPR54, when uncoupled from the G(q/11) pathway, as is the case for several naturally occurring GPR54 mutants associated with hypogonadotropic hypogonadism, continues to regulate gene expression in a G protein-independent manner. These new and exciting findings add significantly to our mechanistic understanding of how this important receptor signals intracellularly in response to kisspeptin stimulation. Public Library of Science 2010-09-23 /pmc/articles/PMC2944883/ /pubmed/20886089 http://dx.doi.org/10.1371/journal.pone.0012964 Text en Szereszewski et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Szereszewski, Jacob M. Pampillo, Macarena Ahow, Maryse R. Offermanns, Stefan Bhattacharya, Moshmi Babwah, Andy V. GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner |
title | GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner |
title_full | GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner |
title_fullStr | GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner |
title_full_unstemmed | GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner |
title_short | GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a Gα(q/11) and β-Arrestin-Dependent Manner |
title_sort | gpr54 regulates erk1/2 activity and hypothalamic gene expression in a gα(q/11) and β-arrestin-dependent manner |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944883/ https://www.ncbi.nlm.nih.gov/pubmed/20886089 http://dx.doi.org/10.1371/journal.pone.0012964 |
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