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.
Highlights
Neuropeptides characterized by a common carboxy-terminal arginine (R) and an amidated phenylalanine (F) motif were originally discovered in invertebrates [1].In mammals it is known that there exist at least five genes, encoding the family members and the five G-protein coupled receptors through which RFamide peptides act
Nowadays the rising number of RFamide peptides found in mammals can be subdivided into five groups: the neuropeptide FF (NPFF) group, the gonadotropin-inhibitory (GnIH) group, the 26RFa group, the kisspeptin/metastin group and the prolactin-releasing peptide (PrRP) group
While the acidic residue 6.59 is conserved throughout the whole RFamide peptide receptor family, in the human kisspeptin receptor an alanine is present at that position
Summary
Neuropeptides characterized by a common carboxy-terminal arginine (R) and an amidated phenylalanine (F) motif (designated RFamide peptides) were originally discovered in invertebrates [1]. In mammals it is known that there exist at least five genes, encoding the family members and the five G-protein coupled receptors through which RFamide peptides act. All these peptides show a great diversity, regarding their N-termini and a wide pattern of biological activity. The first reported vertebrate member was LPLRFamide [2], and the first mammalian RFamide peptides were neuropeptide FF and neuropeptide AF [3] Both were purified from bovine brain extracts [3], showed several biological activities in vivo in mammals [4] and are encoded by a single gene [5]. It should be noted that Hori et al [12] named the same peptide metastin, which derives from its initially discovered function to suppress metastasis, but for clarity kisspeptin is used preferentially in this review
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