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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.

G-Protein Coupled Receptor 83 (GPR83) Signaling Determined by Constitutive and Zinc(II)-Induced Activity