%0 Journal Article
%T GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a G¦Áq/11 and ¦Â-Arrestin-Dependent Manner
%A Jacob M. Szereszewski
%A Macarena Pampillo
%A Maryse R. Ahow
%A Stefan Offermanns
%A Moshmi Bhattacharya
%A Andy V. Babwah
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0012964
%X G protein-coupled receptor 54 (GPR54) is a Gq/11-coupled 7 transmembrane-spanning receptor (7TMR). Activation of GPR54 by kisspeptin (Kp) stimulates PIP2 hydrolysis, Ca2+ 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 Gq/11 and ¦Â-arrestin pathways on the activation of a major downstream signaling molecule, ERK, using Gq/11 and ¦Â-arrestin knockout mouse embryonic fibroblasts. Our study revealed that GPR54 employs the Gq/11 and ¦Â-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 ¦Â-arrestin-2 potentiates GPR54 signaling to ERK, ¦Â-arrestin-1 inhibits it. Our data also revealed that diminished ¦Â-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, ¦Â-arrestin-1 and -2 also regulate distinct downstream responses in gene expression. Finally, we showed that GPR54, when uncoupled from the Gq/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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012964