Abstract
The G-protein coupled receptor 83 (GPR83) is an orphan G-protein coupled receptor for which the natural ligand(s) and signaling pathway(s) remain to be identified. Previous studies suggest a role of GPR83 in the regulation of thermogenesis and the control of circulating adiponectin. The aim of this study was to gain insights into the molecular underpinnings underlying GPR83 signaling. In particular, we aimed to assess the underlying G-protein activated signaling pathway of GPR83 and how this pathway is affected by mutational activation and zinc(II) challenge. Finally, we assessed the capacity of GPR83 for homodimerization. Our results show for the first time that mouse (m) GPR83 has high basal Gq/11 activity without affecting Gi or Gs signaling. Furthermore, we found that, under physiological conditions, zinc(II) (but not calcium(II) and magnesium(II)) potently activates mGPR83, thus identifying zinc(II) as an endogenous molecule with agonistic capability to activate mGPR83. In line with the observation that zinc(II)-ions activate mGPR83, we identified a cluster of ion-binding sensitive amino acids (e.g. His145, His204, Cys207, Glu217) in an activation sensitive receptor region of mGPR83. The occurrence of a constitutive activating mutant and a zinc(II)-binding residue at the N-terminal part corroborate the importance of this region in mGPR83 signal regulation. Finally, our results indicate that mGPR83 forms homodimers, which extend the current knowledge and molecular facets of GPR83 signaling.
Highlights
G-protein coupled receptor 83 (GPR83), previously identified as JP05, GPR72 or the glucocorticoid-induced receptor (GIR) is an orphan G-protein coupled receptor (GPCR) belonging to the rhodopsin-like class A GPCRs [1]
The results revealed that murine GPR83 (mGPR83) did not alter Gs- or Gi-mediated signal activation compared to the negative empty vector control, the Gs positive control or the Gi positive control (Electronic supplementary material, Fig. S2)
In support of this notion, the Cys304Trp mutant increased the accumulation of IP3 2.7 fold compared to mock and by 21% compared to baseline levels of wild type mGPR83 (p,0.001; Fig. 1), confirming the constitutive activity of this mGPR83 mutant
Summary
G-protein coupled receptor 83 (GPR83), previously identified as JP05, GPR72 or the glucocorticoid-induced receptor (GIR) is an orphan G-protein coupled receptor (GPCR) belonging to the rhodopsin-like class A GPCRs [1]. Induction of GPR83 mRNA expression upon dexamethasone [5] or amphetamine [6] treatment suggests a potential role in the regulation of the hypothalamus-pituitary adrenal (HPA) axis. To this extent, GPR83 is most abundantly expressed in the murine brain and the thymus [3]. Former studies showed a selective upregulation of GPR83expression in regulatory T cells (Treg) suggesting a role in development and function of these cells which are important for maintaining immunological tolerance Recently it was shown, that GPR83 is dispensable for Treg cell development and activity [7]. GPR83 expression patterns are similar between rodents and humans [6,9], and there is 87% sequence identity amongst the two species [10]
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