A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice

Abstract

Here, we report the isolation and characterization of an endogenous peptide ligand of GPR103 from rat brains. The purified peptide was found to be the 43-residue RF-amide peptide QRFP. We also describe two mouse homologues of human GPR103, termed mouse GPR103A and GPR103B. QRFP binds and activates the human GPR103, as well as mouse GPR103A and GPR103B, with nanomolar affinities in transfected cells. Systematic in situ hybridization analysis in mouse brains showed that QRFP is expressed exclusively in the periventricular and lateral hypothalamus, whereas the two receptor mRNAs are distinctly localized in various brain areas without an overlap to each other. When administered centrally in mice, QRFP induced feeding behavior, accompanied by increased general locomotor activity and metabolic rate. QRFPinduced food intake was abolished by preadministration of BIBP3226, a specific antagonist for the Y1 neuropeptide Y receptor. Hypothalamic prepro-QRFP mRNA expression was up-regulated upon fasting and in genetically obese ob͞ob and db͞db mice. Central QRFP administration also evoked highly sustained elevation of blood pressure and heart rate. Our findings suggest that QRFP and GPR103A͞B may regulate diverse neuroendocrine and behavioral functions and implicate this neuropeptide system in metabolic syndrome.grooming ͉ hypothalamus ͉ QRFP ͉ wakefulness ͉ metabolic syndrome G protein-coupled receptors (GPCRs) are members of a large protein family that share common structural motifs, including seven transmembrane helices, and play pivotal roles in cell-to-cell communications and in the regulation of cell functions. A large number of GPCRs still remain as ''orphan receptors'' whose cognate ligands have yet to be identified. Identification of ligands for orphan GPCRs provides a basis for understanding the physiological roles of those GPCRs and their ligands, which can involve the central nervous, endocrine, reproductive, cardiovascular, immune, inflammatory, digestive, and metabolic systems.GPR103 (also referred to as SP9155 or AQ27) is an orphan GPCR that shows similarities with orexin, neuropeptide FF, and cholecystokinin receptors. Its mRNA has been detected predominantly in the brain including the cerebral cortex, pituitary, thalamus, hypothalamus, basal forebrain, midbrain, and pons in humans (1). Through bioinformatics approaches, two groups reported putative ligands for GPR103 as a part of a directed effort to identify the precursor genes for a novel RF-amide peptide and its receptor (2, 3). They identified a gene encoding a preproprotein that can be processed into several potential peptides, including a 26-aa (termed P518) and a 43-aa RF-amide peptide (termed QRFP) (2, 3). Both of these peptides activate GPR103, but the 43-aa QRFP exhibited more potent agonistic activity. When intravenously injected into rats, QRFP (43-aa) stimulates aldosterone release (3). The 26-aa RF-amide peptide (termed 26RFa) was independently purified from frog brain by monitoring NPFF-like immunoreactivity (4), and it exhibits orexigenic act...

Positive selection effects on the biochemical properties of mammal pyroglutamylated RFamide peptide receptor (QRFPR)

“…Another point to highlight is the phenomenon of gene duplication, that seems to be related to the evolutionary history of these proteins. This is evident in some species, such as mouse as well as rat, which have two receptor genes as a result of a recent gene duplication (Takayasu et al 2006). Probably this is a characteristic of the rodent lineage and it does not seem to be a generalized phenomenon, although we cannot exclude that other species may have isoforms not yet identified.…”

Hypothalamo-gastrointestinal axis – role in food intake regulation

“…The effect of 26RFa in humans is mediated by GPR103 receptor, which is a 7-transmembrane G protein-coupled receptor (Chartrel et al, 2011). Two distinct forms of GPR103 receptor have been characterized in mice (designated GPR103A and GPR103B) and in rat (designated QRFP-r1 and QRFP-r2) (Kampe et al, 2006;Takayasu et al, 2006). The occurrence of two distinct GPR103 receptors seems to be specific to rodents, as the second gene encoding another form of GPR103 has not been identified in the genome of other vertebrate species (Chartrel et al, 2011).…”

7TM Receptors

“…Prolactin-releasing peptide, GPR10 , hGR3, UHR-1 SP9155 (Jiang et al, 2003), AQ27 (Fukusumi et al, 2003), P518 Ensembl ID ENSG00000116014 ENSG00000148734 ENSG00000056291 ENSG00000119973 ENSG00000186867 Principal transduction G q/11 (Kotani et al, 2001;Muir et al, 2001) G q/11 G i/o (Mollereau et al, 2005) G q/11 (Langmead et al, 2000) G (Takayasu et al, 2006) Leukotriene, lipoxin, oxoeicosanoid and resolvin E1…”