Abstract
BackgroundRecently, the orphan G-protein coupled receptor 83 (GPR83) was identified as a new participant in body weight regulation. This receptor is highly expressed in the hypothalamic arcuate nucleus and is regulated in response to nutrient availability. Gpr83 knock-out mice are protected from diet-induced obesity. Moreover, in a previous study, we designed and characterized several artificial constitutively activating mutations (CAMs) in GPR83. A particular CAM was located in the extracellular N-terminal domain (eNDo) that is highly conserved among GPR83 orthologs. This suggests the contribution of this receptor part into regulation of signaling, which needed a more detailed investigation.FindingsIn this present study, therefore, we further explored the role of the eNDo in regulating GPR83-signaling and demonstrate a proof-of-principle approach in that deletion mutants are characterized by a strong increase in basal Gq/11-mediated signaling, whilst none of the additionally characterized signaling pathways (Gs, Gi, G12/13) were activated by the N-terminal deletion variants. Of note, we detected basal GPR83 MAPK-activity of the wild type receptor, which was not increased in the deletion variants.ConclusionsFinally, the extracellular portion of GPR83 has a strong regulatory function on this receptor. A suppressive - inverse agonistic - effect of the eNDo on GPR83 signaling activity is demonstrated here, which also suggests a putative link between extracellular receptor activation and proteolytic cleavage. These new insights highlight important aspects of GPR83-regulation and might open options in the development of tools to modulate GPR83-signaling.
Highlights
G-protein coupled receptors (GPCRs) are involved in regulating the flow of information across membranes, they are tuning components of the cellular-physiological machinery and serve as hubs for signal transduction between different biological units [1]
A suppressive - inverse agonistic - effect of the extracellular N-terminal domain (eNDo) on G-protein coupled receptor 83 (GPR83) signaling activity is demonstrated here, which suggests a putative link between extracellular receptor activation and proteolytic cleavage
We recently designed several artificial constitutively activating mutations (CAMs) [12], whereby a particular Constitutively activating mutation (CAM) was located in the extracellular N-terminal domain that is highly conserved among GPR83 orthologs
Summary
G-protein coupled receptors (GPCRs) are involved in regulating the flow of information across membranes, they are tuning components of the cellular-physiological machinery and serve as hubs for signal transduction between different biological units [1]. The G-protein coupled receptor 83 (GPR83) [7,8] was recently identified as a new determinant involved in body weight regulation [9] This orphan receptor is most abundantly expressed in the thymus and brain [8,10,11]. The orphan G-protein coupled receptor 83 (GPR83) was identified as a new participant in body weight regulation This receptor is highly expressed in the hypothalamic arcuate nucleus and is regulated in response to nutrient availability. A particular CAM was located in the extracellular N-terminal domain (eNDo) that is highly conserved among GPR83 orthologs This suggests the contribution of this receptor part into regulation of signaling, which needed a more detailed investigation
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