GPR54 Regulates ERK1/2 Activity and Hypothalamic Gene Expression in a G[alpha].sub.q/11 and [beta]-Arrestin-Dependent Manner

• Published in: PloS one 2010-09, Vol.5 (9), p.e12964
• Main Authors: Szereszewski, Jacob M, Pampillo, Macarena, Ahow, Maryse R, Offermanns, Stefan, Bhattacharya, Moshmi, Babwah, Andy V
• Format: Article
• Language: English
• Subjects: Brain; G proteins; Gene expression; Membrane proteins; Physiological aspects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012964

G protein-coupled receptor 54 (GPR54) is a G.sub.q/11 -coupled 7 transmembrane-spanning receptor (7TMR). Activation of GPR54 by kisspeptin (Kp) stimulates PIP.sub.2 hydrolysis, Ca.sup.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.sub.q/11 and [beta]-arrestin pathways on the activation of a major downstream signaling molecule, ERK, using G.sub.q/11 and [beta]-arrestin knockout mouse embryonic fibroblasts. Our study revealed that GPR54 employs the G.sub.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.sub.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.