Research ArticleGPCR SIGNALING

Identification of GPR83 as the receptor for the neuroendocrine peptide PEN

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Science Signaling  26 Apr 2016:
Vol. 9, Issue 425, pp. ra43
DOI: 10.1126/scisignal.aad0694

PEN adopts GPR83

Neuropeptides produced by proteolytic processing of the protein proSAAS include PEN and bigLEN and are implicated in the regulation of appetite. The receptor for bigLEN is GPR171, which was an orphan G protein–coupled receptor (GPCR) until this ligand was identified. Here, Gomes et al. identify the receptor for PEN as the orphan GPCR GPR83, a receptor implicated in behavior, learning, and metabolic regulation. These two ligand-receptor pairs altered each other’s pharmacological properties. Proximity ligation assays and immunofluorescence colocalization assays in mouse brain indicated that the two receptors were present in some of the same cells in the region of the brain that controls feeding. Because PEN and bigLEN are produced from the same precursor, they are sometimes packaged in the same vesicles and are released together. GPR83 also colocalizes and functionally interacts with the receptor for ghrelin, another peptide involved in regulation of organismal metabolism by the central nervous system. Knowing the ligand for GPR83 will enable the investigation of how GPR83, GPR171, and other receptors interact to control body weight, which has implications for treating metabolic disorders associated with being underweight or overweight.


PEN is an abundant peptide in the brain that has been implicated in the regulation of feeding. We identified a receptor for PEN in mouse hypothalamus and Neuro2A cells. PEN bound to and activated GPR83, a G protein (heterotrimeric guanine nucleotide)–binding protein)–coupled receptor (GPCR). Reduction of GPR83 expression in mouse brain and Neuro2A cells reduced PEN binding and signaling, consistent with GPR83 functioning as the major receptor for PEN. In some brain regions, GPR83 colocalized with GPR171, a GPCR that binds the neuropeptide bigLEN, another neuropeptide that is involved in feeding and is generated from the same precursor protein as is PEN. Coexpression of these two receptors in cell lines altered the signaling properties of each receptor, suggesting a functional interaction. Our data established PEN as a neuropeptide that binds GPR83 and suggested that these two ligand-receptor systems—PEN-GPR83 and bigLEN-GPR171—may be functionally coupled in the regulation of feeding.

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