Identification of GPR83 as the receptor for the neuroendocrine peptide PEN

Gomes, Ivone; Bobeck, Erin N.; Margolis, Elyssa B.; Gupta, Achla; Sierra, Salvador; Fakira, Amanda K.; Fujita, Wakako; Müller, Timo; Müller, Anne; Tschöp, Matthias H.; Kleinau, Gunnar; Fricker, Lloyd D.; Devi, Lakshmi A.

doi:10.1126/scisignal.aad0694

Cited by 69 publications

(124 citation statements)

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“…Previous immunohistochemical analysis showed that GPR171 is present in the PVN of the hypothalamus and colocalized with its ligand b-LEN in a subset of cells (6, 27), consistent with a role for GPR171 in feeding. We monitored the effect of MS0015203 on c-Fos abundance as an indication of increased neuronal activity in the PVN 30 min after intraperitoneal injection of MS0015203 in mice (Fig.…”

Section: Resultssupporting

confidence: 56%

“…Rabbit antibodies to GPR171 were from GeneTex (catalog #GTX108131). Rat antibodies to GPR171 were generated using the amino acid sequence MTNSSFFCPVYand tested for specificity using a standard protocol (38) in CHO cells alone or expressing myc-tagged mGPR1 71, or in Neuro2A cells alone or expressing either myc-tagged mGPR171 or GPR171 shRNA (27). Mouse c-Fos antibody (catalog #C3012) was from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

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Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

et al. 2016

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Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide–binding protein (G protein)– coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)–mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders.

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Section: Resultssupporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

et al. 2016

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“…However, NPY receptor binding has not been shown to induce signaling at GPR83. In contrast, the neuropeptide PEN was recently described as a potent GPR83 ligand [9]. In addition, murine GPR83 basal inositolphosphate (IP) formation is increased by treatment with zink ions (Zn 2+ ) or/and several constitutively Gq activating mutations have been designed and characterized [10], including an N-terminal deletion variant, which suggested a potential role of the N-terminus as an intra-molecular antagonist [11].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, homo- and hetero-oligomerization with the ghrelin-receptor (GHSR) was described for mGPR83 and this interaction diminishes GHSR activation by acyl-ghrelin [5]. Hetero-oligomerization and a mutual functional impact of GPR83 with GPR171, a receptor for the peptide bigLEN, have also recently been shown [9]. …”

Section: Introductionmentioning

confidence: 99%

Insights into Basal Signaling Regulation, Oligomerization, and Structural Organization of the Human G-Protein Coupled Receptor 83

et al. 2016

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The murine G-protein coupled receptor 83 (mGPR83) is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR) such as the ghrelin receptor (GHSR) or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo) of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function. Here, we investigated particular amino acids at the eNDo of human GPR83 (hGPR83) by side-directed mutagenesis to identify determinants of the internal ligand. These studies were accompanied by structure homology modeling to combine functional insights with structural information. The capacity for hetero-oligomer formation of hGPR83 with diverse family A GPCRs such as the melanocortin-4 receptor (MC4R) was also investigated, with a specific emphasis on the impact of the eNDo on oligomerization and basal signaling properties. Finally, we demonstrate that hGPR83 exhibits an unusual basal signaling for different effectors, which also supports signaling promiscuity. hGPR83 interacts with a variety of hypothalamic GPCRs such as the MC4R or GHSR. These interactions are not dependent on the ectodomain and most likely occur at interfaces constituted in the transmembrane regions. Moreover, several amino acids at the transition between the eNDo and transmembrane helix 1 were identified, where mutations lead also to biased basal signaling modulation.

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“…Mammalian proSAAS, which is not glycosylated or phosphorylated (14), undergoes proteolytic cleavage at several pairs of basic residues, leaving a core region intact (15,16); recent evidence shows that several processed peptides function as neuropeptides with specific receptors (17,18). ProSAAS is expressed almost exclusively in neurons and neuroendocrine and endocrine cells, and it appears to be restricted to vertebrates (19)(20)(21)(22).…”

mentioning

confidence: 99%

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Jarvela

Lam

Helwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

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Identification of GPR83 as the receptor for the neuroendocrine peptide PEN

Cited by 69 publications

References 53 publications

Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

Insights into Basal Signaling Regulation, Oligomerization, and Structural Organization of the Human G-Protein Coupled Receptor 83

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

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