Identification of Natural Ligands for the Orphan G Protein-coupled Receptors GPR7 and GPR8

Brézillon, Stéphane; Lannoy, Vincent; Franssen, Jean-Denis; Poul, Emmanuel Le; Dupriez, Vincent; Lucchetti, J.; Detheux, Michel; Parmentier, Marc

doi:10.1074/jbc.m206396200

Cited by 111 publications

(154 citation statements)

References 30 publications

(44 reference statements)

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“…One reason could be that G qi5 , an artificial chimeric G-protein, does not couple to all G i -linked GPCRs. We have observed a similar phenomenon when we studied GPR7 and GPR8 (18,19), two highly related neuropeptide W receptors linked to cAMP inhibition. Whereas neuropeptide W stimulated Ca 2ϩ mobilization in HEK293 cells co-expressing GPR7 and G qi5, it did not do the same for cells co-expressing GPR8 and G qi5 .…”

Section: Discussionmentioning

confidence: 70%

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Liu

Chen

Sutton

et al. 2003

Journal of Biological Chemistry

226

272

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We have recently identified the insulin-like peptide relaxin-3 (aka INSL7) as the endogenous ligand for an orphan G-protein-coupled receptor, GPCR135 (aka somatostatin-and angiotensin-like peptide receptor). Analysis of possible receptors related to GPCR135 revealed a single orphan receptor, GPCR142. Thus, we tested whether GPCR142 could also respond to relaxin-3 or related insulin-like molecules. Surprisingly, GPCR142 was activated by nanomolar concentrations of relaxin-3 but was completely unresponsive to all other known insulin-like peptides. We evaluated by reverse transcriptase-PCR the expression of GPCR142 mRNA in a variety of human tissues and found expression in brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid, and colon. In an analysis of other species, we were able to find a full-length mouse homolog of GPCR142, but were unable to detect any complete GPCR142 transcripts in rat. With respect to intracellular signaling, GPCR142 is similar to GPCR135 in that it potently inhibits adenylate cyclase and stimulates 35 S-GTP␥S incorporation in response to relaxin-3. However, whereas GPCR135 signaling could be converted to calcium mobilization using a G qi5 or G␣ 16 G-proteins, GPCR142 was only capable of functioning in the presence of G␣ 16 . In the accompanying article (Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jö rnvall, H., Sillard, R., and Lovenberg, T. W. (2003) J. Biol. Chem. 278, 50754 -50764), we present the case that relaxin-3, which has previously been shown to bind to the relaxin receptor LGR7, is most likely the endogenous ligand for GPCR135. In this report, we show an additional receptor, GPCR142, which is also selectively activated by relaxin-3. However, the anatomical localization of GPCR142 suggests that GPCR142 may have different physiological functions.Relaxin-3 (1) is a member of the insulin superfamily, where each member consists of two peptide subunits arranged by three disulfide bridges. Recently, two leucine-rich repeat-containing G-protein-coupled receptors (LGRs), 1 LGR7 and LGR8 (2, 3), have been identified as the receptors for relaxin (3-7).LGR7 and LGR8 belong to the type III hormone receptor family (follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid stimulating hormone (TSH) etc. that stimulate adenylate cyclase). Relaxin-3 was recently demonstrated to be an additional ligand for the relaxin receptor LGR7, but not LGR8 (8). Instead, the ligand INSL3 (9), another member of the insulin/relaxin family of peptides, has been shown to be an additional ligand for LGR8 (10).As part of a directed effort to identify ligands for orphan G-protein-coupled receptors (GPCRs), we established a systematic program to create tissue extracts as a source of possible GPCR ligands. In the accompanying article (23), we report the purification and identification of the peptide ligand, relaxin-3, as an endogenous ligand for orphan receptor GPCR135, aka SALPR (somatostatin-and angiotensin-like peptide receptor).In that report...

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Section: Discussionmentioning

confidence: 70%

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Liu

Chen

Sutton

et al. 2003

Journal of Biological Chemistry

226

272

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“…As known, both neuropeptides and their receptors are structurally highly homologous and this suggests that each ligand and receptor are partially overlapping and also have specific roles in this signaling system. As demonstrated, NPB activates and binds to both human NPBWR1 (with higher affinity) and NPBWR2, and similar effects are demonstrated with NPW23 and NPW30, with NPBWR1 binding with lower affinity (6,8). Previous observations revealed notable differences in NPB and NPW action on both rat and human adrenocortical cells (18,20,24).…”

Section: Discussionmentioning

confidence: 92%

“…The amino acid sequence of NPW23 is identical to the first 23 Nterminal amino acids of NPW30 (4,5). Expression of NPB, NPW and their receptor gene was found to be present in the central nervous system and in the peripheral organs of humans, rats, and mice (1,2,(5)(6)(7)(8)(9). Distribution of the gene expression within the brain suggests that NPB plays a role in the control of feeding and neuroendocrine axis functions, as well as in memory and learning processes.…”

Section: Introductionmentioning

confidence: 87%

“…Both at the level of mRNA and protein, expression of NPB and NPW and their receptors in human and rat endocrine glands and hypothalamus have been well documented (6,(16)(17)(18)(19)(20)(21). Concerning the functional role of the NPB-NPW system, a growing body of evidence indicates that this system is involved in the regulation of neuroendocrine axis activity.…”

Section: Discussionmentioning

confidence: 99%

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Neuropeptide W exerts a potent suppressive effect on blood leptin and insulin concentrations in the rat

Ruciński

Nowak²,

Chmielewska³

et al. 2007

Int J Mol Med

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Abstract. Neuropeptide B/W receptor 1 (NPBWR1) and neuropeptide B/W receptor 2 (NPBWR2) are two structurally related orphan receptors linked to protein G. In rodents NPBWR2 is absent, and its counterpart is described as being similar to neuropeptide B/W receptor 2. Endogenous ligands of these receptors have been identified. One of them is 29 amino acid residues long, uniquely modified with bromine and, thus, termed neuropeptide B (NPB). The other, neuropeptide W (NPW), has been identified in two molecular forms of 23 and 30 amino acids (NPW23 and NPW30), respectively. Both NPB and NPW affect food intake and energy expenditure. Since leptin, a potent anti-obesity hormone, and insulin are involved in the control of energy homeostasis, the present study aimed to investigate whether NPB and NPW affect leptin and insulin secretion in the rat. RT-PCR technique revealed the presence of ppNPB, ppNPW, NPBWR1 and NPBWR2-like mRNAs in isolated pancreatic islets of the rat. NPB and NPW immunoreactivities were observed in all of the cells of the pancreatic islets. Only when a higher dose was administered (3 nmol/100 g body weight) did NPW transiently lower blood insulin levels whereas NPB injection did not alter insulinaemia in the studied rats. At 30 min, but not 60, of the experiment, NPW notably lowered blood leptin concentrations at both tested doses. On the contrary, NPB injections had no effect on blood leptin and insulin concentrations. Thus, the results suggest that NPW but not NPB exerts a potent suppressive effect on blood leptin concentrations in the rat, and this mechanism may be involved in NPW regulation of energy homeostasis.

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“…In rodents GPR8 is absent, its counterpart being described as GPR8-like receptor (GPR8-LR) (3). NPB, NPW and their receptors are highly expressed in the human and rodent central nervous system (especially hypothalamus) (1)(2)(3)(4)(5)(6)(7)(8), and findings have been accumulated that these peptides are involved in the central regulation of feeding behavior and energy homeostasis (6,(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Expression of neuropeptides B and W and their receptors in endocrine glands of the rat

Hochol¹,

Belloni²,

Ruciński³

et al. 2006

Int J Mol Med

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Abstract. Neuropeptides B and W (NPB and NPW) have been identified as endogenous ligands of the G protein-coupled receptors (GPR) 7 and 8, which in humans are expressed in the hypothalamus and probably involved in the regulation of energy homeostasis and feeding behavior. GPR8 is absent in the rat, where the GPR8-like receptor (GPR8-LR) has been described. Reverse transcription-polymerase chain reaction detected the expression of NPB, NPW, GPR7 and GPR8-LR mRNAs in the hypothalamus, anterior pituitary, thyroid and parathyroid glands, pancreatic islets, adrenal glands, ovary and testis of the rat. Immunocytochemistry demonstrated the presence of NPB and NPW immunoreactivities in these same glands. Radioimmune assay showed that the bolus intraperitoneal injection of 2 nmol/100 g NPB or NPW raised the plasma levels of parathyroid hormone, corticosterone and testosterone. NPB also increased the blood concentration of thyroxine, and NPW that of ACTH and estradiol. Taken together, these findings allow us to suggest that NPB and NPW play a role in the autocrine-paracrine functional regulation of the endocrine system in the rat.

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Identification of Natural Ligands for the Orphan G Protein-coupled Receptors GPR7 and GPR8

Cited by 111 publications

References 30 publications

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Neuropeptide W exerts a potent suppressive effect on blood leptin and insulin concentrations in the rat

Expression of neuropeptides B and W and their receptors in endocrine glands of the rat

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