Endocrine Abstracts (2012) 29 P1208

GPR83 in interaction with GHSR and MC3R: lessons from in vitro studies

A. Müller1, T. Müller2, G. Kleinau1, A. Grüters-Kieslich1, H. Krude1, M. Tschöp2,3 & H. Biebermann1

1Institute of Experimental Pediatric Endocrinology, Berlin, Germany; 2Institute for Diabetes and Obesity, Neuherberg, Germany; 3Dept. of Metabolic Diseases, Munich, Germany.

GPR83 is an orphan G-protein coupled receptor (GPCR) and is expressed in thymus and brain. Within the brain GPR83 mRNA is identified at high levels in the hypothalamic arcuate nucleus that is known to control for body weight regulation.

Expression of GPR83 in the arcuate nucleus and the protection of GPR83 knock-out mice against diet induced obesity prompted us to investigate GPR83 signaling properties as well as potential interaction with the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR). Both receptors are also localized in the arcuate nucelus and they are known to be key-players of body weight regulation. Recently we demonstrated that MC3R and GHSR are able to form heterodimers which modulates mutually the signaling properties of both receptors.

In this study investigation of cAMP accumulation and IP3 formation in vitro revealed no basal activity of GPR83 in Gs nor Gi, but significant basal activity in Gq/11 mediated signaling. Due to unknown GPR83 ligands we designed and tested a potential constitutively active mutant in transmembrane helix 6 and confirmed thereby activation of Gq/11 signaling. To test for GPR83/MC3R and GPR83/GHSR heterodimerization a sandwich ELISA as well as Yellow fluorescent protein complementation assay were utilized and both methods confirmed interaction of GPR83 with MC3R or GHSR in vitro. Functional characterization of the GPR83/MC3R and GPR83/GHSR heterodimers in coexpression studies revealed a modification of signaling properties compared to monomers or homodimers: down-regulation of GHSR signaling in response to ghrelin and up-regulation of MC3R in response to its ligands alpha- and gamma-MSH.

In conclusion, GPR83 might be a new important key-player in hypothalamic body weight regulation and could therefore represent a value target to modulate energy metabolism. This receptor couples intracellularly to Gq and is able to modify by formation of heterodimers the signaling capacities of MC3R and GHSR.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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