RFamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential

Abstract

Different neuropeptides, all containing a common carboxy-terminal RFamide sequence, have been characterized as ligands of the RFamide peptide receptor family. Currently, five subgroups have been characterized with respect to their N-terminal sequence and hence cover a wide pattern of biological functions, like important neuroendocrine, behavioral, sensory and automatic functions. The RFamide peptide receptor family represents a multiligand/multireceptor system, as many ligands are recognized by several GPCR subtypes within one family. Multireceptor systems are often susceptible to cross-reactions, as their numerous ligands are frequently closely related. In this review we focus on recent results in the field of structure-activity studies as well as mutational exploration of crucial positions within this GPCR system. The review summarizes the reported peptide analogs and recently developed small molecule ligands (agonists and antagonists) to highlight the current understanding of the pharmacophoric elements, required for affinity and activity at the receptor family. Furthermore, we address the biological functions of the ligands and give an overview on their involvement in physiological processes. We provide insights in the knowledge for the design of highly selective ligands for single receptor subtypes to minimize cross-talk and to eliminate effects from interactions within the GPCR system. This will support the drug development of members of the RFamide family.

Selective Mode of Action of Guanidine-Containing Non-Peptides at Human NPFF Receptors

“…8 Accordingly, interaction partners in the receptors should be aromatic or acidic residues. Owing to the knowledge from the closely related neuropeptide Y system, 23,24 either aromatic or acidic or polar residues in the extracellular loops 2 and 3, and in the upper region of the TM helices V, VI or VII were selected and individually replaced by Ala (Figure 3).…”

“…1 The NPFF receptor system is involved in numerous physiological functions such as cardiovascular actions, 2,3 regulation of body temperature 4,5 and water balance. 6,7 As NPFF plays an important role in the modulation of pain and the regulation of the opioid system, it represents a peptide with strong therapeutic potential (for review see Findeisen et al , 2011 8 ). Despite these findings, there is no significant affinity of NPFF for any of the opiate receptor subtypes.…”

Discovery by proteogenomics and characterization of an RF-amide neuropeptide from cone snail venom

“…In mammals RF-amide distribution patterns appear to be limited to specific brain areas where they are involved in essential functions such as cardiovascular regulation, pain modulation and food consumption. To date, RF-amides from five precursors have been characterized in humans [25]: neuropeptides FF (NPFF) and AF (NPAF) [26], Prolactin-releasing peptide (PrRP) [27], RFRPs 1 and 3 [28], 26RFa [29], and the kisspeptins [30]. Most of the neuronal actions of RF-amides appear to be mediated through specific GPCRs [27, 28, 30–33], although two ionotropic receptors for these peptides have been reported [34, 35], viz the invertebrate FMRF-amide-gated Na + channel (FaNaC) and the related mammalian acid-sensing ion channels (ASICs).…”

The effects of high fat diet and estradiol on hypothalamic prepro-QRFP mRNA expression in female rats

“…Central administration of QRFP-26 selectively increases high fat diet (HFD) intake, without altering low fat diet (LFD) intake in intact female rats (Primeaux, 2011; Primeaux et al, 2013). Both QRFP-26 and QRFP-43 are potent ligands for the G protein-coupled receptors, QRFP-r1 and QRFP-r2 (GPR103a and GPR103b in mouse), which are expressed throughout the brain (Chartrel et al, 2003; do Rego et al, 2006; Findeisen et al, 2011; Lectez et al, 2009; Moriya et al, 2006; Navarro et al, 2006; Patel et al, 2008; Primeaux, 2011; Primeaux et al, 2013; Primeaux et al, 2008; Takayasu et al, 2006; Ukena et al, 2014; Ukena et al, 2010; Ukena et al, 2013; Ukena et al, 2011). Within appetite regulation centers of the hypothalamus, QRFP-r1 is primarily expressed in the VMH/ARC, while QRFP-r2 is primarily expressed in the LH (Leprince et al, 2013).…”