Review
The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions

https://doi.org/10.1016/j.yfrne.2011.04.001Get rights and content

Abstract

Identification of novel neuropeptides and their cognate G protein-coupled receptors is essential for a better understanding of neuroendocrine regulations. The RFamide peptides represent a family of regulatory peptides that all possess the Arg-Phe-NH2 motif at their C-terminus. In mammals, seven RFamide peptides encoded by five distinct genes have been characterized. The present review focuses on 26RFa (or QRFP) which is the latest member identified in this family. 26RFa is present in all vertebrate phyla and its C-terminal domain (KGGFXFRF-NH2), which is responsible for its biological activity, has been fully conserved during evolution. 26RFa is the cognate ligand of the orphan G protein-coupled receptor GPR103 that is also present from fish to human. In all vertebrate species studied so far, 26RFa-expressing neurons show a discrete localization in the hypothalamus, suggesting important neuroendocrine activities for this RFamide peptide. Indeed, 26RFa plays a crucial role in the control of feeding behavior in mammals, birds and fish. In addition, 26RFa up-regulates the gonadotropic axis in mammals and fish. Finally, evidence that the 26RFa/GPR103 system regulates steroidogenesis, bone formation, nociceptive transmission and arterial blood pressure has also been reported. Thus, 26RFa appears to act as a key neuropeptide in vertebrates controlling vital neuroendocrine functions. The pathophysiological implication of the 26RFa/GPR103 system in human is totally unknown and some fields of investigation are proposed.

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.

References (79)

  • P. Ducy et al.

    Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass

    Cell

    (2000)
  • E.M. Egido et al.

    26RFa, a novel orexigenic neuropeptide, inhibits insulin secretion in the rat pancreas

    Peptides

    (2007)
  • F. Elefteriou et al.

    Bone mass regulation by leptin: a hypothalamic control of bone formation

    Pathol. Biol. (Paris)

    (2004)
  • N.A. Elshourbagy et al.

    Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor

    J. Biol. Chem.

    (2000)
  • Q. Fang et al.

    Cardiovascular effects of intravenous administered 26RFa, a novel RFamide peptide ligand for GPR103, in anaesthetized rats

    Eur. J. Pharmacol.

    (2009)
  • S. Fukusumi et al.

    Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP

    Peptides

    (2006)
  • S. Fukusumi et al.

    A new peptidic ligand and its receptor regulating adrenal function in rats

    J. Biol. Chem.

    (2003)
  • P. Gorwood et al.

    The human genetics of anorexia nervosa

    Eur. J. Pharmacol.

    (2003)
  • C. Gouardères et al.

    Functional differences between NPFF1 and NPFF2 receptor coupling: High intrinsic activities of RFamide-related peptides on stimulation of [35S]GTPγS binding

    Neuropharmacology

    (2007)
  • Y. Jiang et al.

    Identification and characterization of a novel RF-amide peptide ligand for orphan G-protein-coupled receptor SP9155

    J. Biol. Chem.

    (2003)
  • J. Kampe et al.

    Effect of central administration of QRFP(26) peptide on energy balance and characterization of a second QRFP receptor in rat

    Brain Res.

    (2006)
  • G. Koch et al.

    The actions of neuroactive peptides on the isolated heart of the giant African snail, Achatina fulica

    Comp. Biochem. Physiol. C

    (1993)
  • D.K. Lee et al.

    Discovery and mapping of ten novel G protein-coupled receptor genes

    Gene

    (2001)
  • C. Li et al.

    FMRFamide-related neuropeptide gene family in Caenorhabditis elegans

    Brain Res.

    (1999)
  • Y. Liu et al.

    Molecular cloning and functional characterization of the first non-mammalian 26RFa/QRFP orthologue in goldfish, Carassius auratus

    Mol. Endocrinol.

    (2009)
  • T. Murase et al.

    Neuropeptide FF reduces food intake in rats

    Peptides

    (1996)
  • R. Nichols et al.

    Human RFamide-related peptide-1 diminishes cellular and integrated cardiac contractile performance

    Peptides

    (2010)
  • R. Pineda et al.

    Physiological role of the kisspeptin/GPR54 system in the neuroendocrine control of reproduction

    Prog. Brain Res.

    (2010)
  • S.D. Primeaux et al.

    Central administration of the RFamide peptides, QRFP-26 and QRFP-43, increases high fat food intake in rats

    Peptides

    (2008)
  • T. Sakurai et al.

    Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behaviour

    Cell

    (1998)
  • M. Schaefer et al.

    Aplysia neurons express a gene encoding multiple FMRFamide neuropeptides

    Cell

    (1985)
  • C.M. Steppan et al.

    Leptin is a potent stimulator of bone growth in ob/ob mice

    Regul. Pept.

    (2000)
  • D. Sunter et al.

    Intracerebroventricular injection of neuropeptide FF, an opioid modulating neuropeptide, acutely reduces food intake and stimulates water intake in the rat

    Neurosci. Lett.

    (2001)
  • R. Thuau et al.

    Structural studies on 26RFa, a novel human RFamide-related peptide with orexigenic activity

    Peptides

    (2005)
  • K. Tsutsui et al.

    Gonadotropin-inhibitory hormone (GnIH) and its control of central and peripheral reproductive function

    Front. Neuroendocrinol.

    (2010)
  • T. Yamamoto et al.

    Analgesic effects of intrathecally administered 26RFa, an intrinsic agonist for GPR103, on formalin test and carrageenan test in rats

    Neuroscience

    (2008)
  • T. Yamamoto et al.

    Intracerebroventricular administration of 26RFa produces an analgesic effect in the rat formalin test

    Peptides

    (2009)
  • A. Yamanaka et al.

    Orexin-induced food intake involves neuropeptide Y pathway

    Brain Res.

    (2000)
  • Q. Zhang et al.

    P518/Qrfp sequence polymorphisms in SAMP6 osteopenic mouse

    Genomics

    (2007)
  • Cited by (54)

    • Pyroglutamylated RFamide peptide

      2021, Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research
    • Microinjection of 26RFa, an endogenous ligand for the glutamine RF-amide peptide receptor (QRFP receptor), into the rostral ventromedial medulla (RVM), locus coelureus (LC), and periaqueductal grey (PAG) produces an analgesic effect in rats

      2019, Peptides
      Citation 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].

    • Anxiolytic effect of the GPR103 receptor agonist peptide P550 (homolog of neuropeptide 26RFa) in mice. Involvement of neurotransmitters

      2016, Peptides
      Citation 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].

    View all citing articles on Scopus
    View full text