ReviewThe RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions
Highlights
► 26RFa is a novel vertebrate RFamide peptide. ► 26RFa is the endogenous ligand of the human orphan receptor GPR103. ► 26RFa stimulates food intake in mammals, birds and fish. ► 26RFa up-regulates the gondatropic axis in mammals and fish. ► 26RFa also regulates steroidogenesis, bone formation and nociceptive transmission.
Introduction
More than 30 years have passed since the isolation of the tetrapeptide FMRFamide from the ganglia of the venus clam Macrocallista nimbosa [59]. Since then, a number of peptides sharing the C-terminal RFamide signature have been characterized in virtually all invertebrate phyla [12], [15], indicating that FMRFamide was just one member of a large family of biologically active peptides collectively termed the RFamide peptides. In various molluscan species, molecular cloning has revealed the occurrence of multiple RFamide peptide genes within a single species and that multiple copies of RFamide peptides may be generated by a single precursor [47], [48], [64]. RFamide peptides have been found to exert a large array of biological activities in invertebrates, including cardioexcitatory activities [41], [46], [61], modulation of muscle contraction [9], control of locomotor activity [55], regulation of water balance [63] and neuromodulatory activities [1], [17]. Immunohistochemical studies using antibodies directed against FMRFamide had long suggested that RFamide peptides also exist in vertebrates [18], [75]. Indeed, several RFamide peptides have been identified in fish, amphibians and birds [15], and to date seven RFamide peptides encoded by five distinct genes have been characterized in mammals [14]. Neuropeptide FF (NPFF) and neuropeptide AF (NPAF) have been isolated from a bovine brain extract using antibodies directed against FMRFamide. Prolactin-releasing peptide (PrRP) and kisspeptin have been purified from bovine hypothalamic and human placenta extracts, and identified by reverse pharmacology as the endogenous ligands of the human orphan receptors GPR10 and GPR54, respectively. A search for additional members of the RFamide peptide family in various databases has led to the identification of two human expressed sequence tags (ESTs) that encode two RFRPs designated RFamide-related peptide-1 and -3 (RFRP-1 and -3). Finally, the precursor of a novel RFRP initially isolated from a frog brain extract, referred to as 26RFa or QRFP, has been characterized in several mammalian species. All these RFamide peptides have been subsequently shown to exert major neuroendocrine functions in mammals [14], [15], [30], [72]. In the present review, we will focus on 26RFa which is the latest member of the RFamide peptide family discovered in mammals. We will review what is currently known about vertebrate 26RFa homologs, 26RFa receptors and the functions of this novel neuropeptide with special emphasis on its neuroendocrine activities.
Section snippets
Discovery of 26RFa
The discrepancy between the number of RFamide peptides characterized in invertebrates and that known in vertebrates raised the possibility that additional RFamide peptides remained to be identified in mammals. 26RFa is one of these peptides that was discovered simultaneously by three different groups in 2003 [13], [31], [38]. Distinct strategies have been developed by the three groups to isolate this 26-amino acid peptide. Our own group has used a comparative approach based on the purification
Identification of the 26RFa receptor
26RFa has been identified as the endogenous ligand of the human orphan receptor GPR103, also referred to as SP9155 or AQ27 [31], [38]. GPR103 is a 7-transmembrane G protein-coupled receptor (GPCR) that shares significant amino acid identity (52%) with NPFF2 [8], [45], another receptor for mammalian RFamide peptides. This high sequence identity between GPR103 and NPFF2 suggested that the endogenous ligand of GPR103 could be an RFamide peptide. 26RFa and 43RFa were thus good candidates as cognate
Tissue distribution of 26RFa
Expression of the 26RFa gene has been investigated in various mammalian, bird and fish species. Quantitative PCR experiments have revealed that, in all vertebrate species with the exception of human, the highest levels of the 26RFa transcript are detected in the hypothalamus [31], [38], [49], [68], [73]. Detailed localization using in situ hybridization and immunocytochemical approaches have shown that, in human, 26RFa-containing neurons are present in the ventromedial hypothalamic nucleus and
Control of food intake
26RFa-expressing neurons display a discrete localization in hypothalamic nuclei, in all vertebrate species studies so far, such as the ventromedial hypothalamic nucleus, the lateral hypothalamic area and the arcuate nucleus, which are all known to be involved in the regulation of food intake. GPR103 is also found in the same hypothalamic structures and in other brain nuclei such as the piriform cortex and the nucleus of the solitary tract also involved in the regulation of food consumption.
Conclusion and pathophysiological perspectives
The discovery of 26RFa from the frog brain, its subsequent characterization in various mammalian species, birds and fish, and the presence of a homologous sequence to 26RFa in the genome of the lizard [49] indicate that 26RFa is present in all vertebrate phyla. Evolutionary pressure has acted to fully conserve the C-terminal region KGGFXFRF-NH2 of 26RFa that is responsible for the biological activity of the neuropeptide [see above]. 26RFa is the first representative of a novel subfamily of
Acknowledgments
This work was supported by INSERM (U982), the University of Rouen, the LARC-Neuroscience network, the Association pour la Recherche sur les Tumeurs Prostatiques (ARTP), the Plateforme Régionale de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN) and the Conseil Régional de Haute-Normandie.
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2019, PeptidesCitation Excerpt :26RFa-expressing neurons have discrete localization in the hypothalamus. 26RFa acts as a key neuropeptide in vertebrates to control vital neuroendocrine functions [3]. 26RFa/QRFP knockout mice are markedly hypophagic, lean, and have increased anxiety-like behaviors [12].
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2018, Biomedicine and PharmacotherapyAnxiolytic effect of the GPR103 receptor agonist peptide P550 (homolog of neuropeptide 26RFa) in mice. Involvement of neurotransmitters
2016, PeptidesCitation Excerpt :The GPR103 is a “deorphanized” Gαi/o and Gαq protein-coupled receptor that has a single encoding gene in humans, whereas there are two isoforms, designated as GPR103A and GPR103B in rodents [5,8,41,42]. The 43RFa and the 26RFa bind to both isoforms with nearly similar affinity [5,41]. GPR103 expression was detected in several brain regions, including the paraventricular and magnocellular hypothalamic nuclei, striatum, bed nucleus of stria terminalis (BNST), lateral septum (LS), medial supramammillary nucleus, olfactory bulb as well as in the brainstem in rodents [3,34].