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Document Version Version Comment Date Status
559843.0 Automatic journal name synchronization 02.04.2011 20:15 Released

ID: 559843.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
GPR54 regulates ERK1/2 activity and hypothalamic gene expression in a Galpha(q/11) and beta-arrestin-dependent manner
Authors:Szereszewski, J. M.; Pampillo, M.; Ahow, M. R.; Offermanns, S.; Bhattacharya, M.; Babwah, A. V.
Title of Journal:PLoS ONE
Issue / Number:9
Start Page:e12964
Audience:Not Specified
Abstract / 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 beta-arrestin pathways on the activation of a major downstream signaling molecule, ERK, using G(q/11) and beta-arrestin knockout mouse embryonic fibroblasts. Our study revealed that GPR54 employs the G(q/11) and beta-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 beta-arrestin-2 potentiates GPR54 signaling to ERK, beta-arrestin-1 inhibits it. Our data also revealed that diminished beta-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, beta-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.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:The Children's Health Research Institute, London, Ontario, Canada.
Identifiers:ISSN:1932-6203 (Electronic) 1932-6203 (Linking)