Prolactin-Releasing Peptide: Physiological and Pharmacological Properties

Abstract

Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.

Keywords: GPR10; RF-amide peptides; energy expenditure; food intake regulation; neuroprotection; prolactin-releasing peptide; signaling.

Figure 1

Distribution of PrRP and GPR10. Ellipses represent distinct brain areas (blue—nucleus accumbens, grey—corpus callosum, green—hippocampus, red—thalamus, orange—hypothalamus, yellow—pituitary, violet—parabrachial nucleus, light green—medulla oblongata). Stars mark the expression of mRNA (red star—PrRP, black star—GPR10). Spots represent the distribution of PrRP (red), GPR10 (black) cell bodies and fibers. AP: area postrema, C: cerebral cortex, CC: corpus callosum, CE: cerebellum, DMN: dorsomedial hypothalamic nucleus, HB: hindbrain, HIPP: hippocampus, HYP: hypothalamus, LHA: lateral hypothalamic area, ME: medulla oblongata, MIB: midbrain, NAc: nucleus accumbens, NTS: nucleus of the solitary tract, OF: olfactory bulb, P: pituitary, PB: parabrachial nucleus, PEVN: periventricular hypothalamic nucleus, PVN: paraventricular hypothalamic nucleus, RT: reticular nucleus of the thalamus, SON: supraoptic nucleus, SLM: stratum lacunosum-moleculare, TH: thalamus, VMN: ventromedial hypothalamic nucleus, VRT: ventrolateral reticular nucleus of the thalamus.

Figure 2

PrRP physiological functions and signaling—summary. PrRP and its agonist exerts its effect through GPR10. Blue arrow represents activation of the signaling pathway, T-bar represents blocking of the signaling pathway. PrRP stimulated calcium release (Ca²⁺) in calcium mobilization assay and rapidly activated extracellular signal-regulated protein kinase (ERK – blue). It also activated c-Jun N-terminal protein kinase (JNK—light blue) and phosphorylated cAMP response element-binding protein (CREB—grey). Pertussis toxin (PTX—black) blocked the ERK and Akt activation induced by PrRP. PrRP activated the PI3K B/Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathways in leiomyoma cells (PI3K—pink, PKB/Akt—green,.mTOR—yellow). PrRP significantly stimulated both the PKA (dark green) and PKC (orange) pathways.

Figure 3

Structure of PrRP20 and PrRP31 and its analogs [31,55,56,58,65,67]. Blue amino acid Ser¹ marks the beginning of PrRP31 from the N-terminus. Blue amino acid Thr¹² marks the beginning of shorter isoform PrRP20 (also known as PrRP(12–31)). Blue amino acid Trp¹⁹ marks tridecapeptide PrRP(19–31) and blue Ile²⁵ marks the shortest fragment heptapeptide PrRP(25–31). Green amide group NH₂ and green Arg²³, Arg²⁶, Arg³⁰, and Phe³¹ amino acids are essential for the functionality of the peptide. Light grey amino acids mark changes of amino acids that preserved good functional activity. Dark grey Arg¹¹ could be substituted by Lys¹¹ and its secondary amino group, fatty acids, were attached through different linkers. γ-E: γ-glutamic acid, MEG-FA: multiple ethylene glycol-fatty acid (four ethylene glycol units attached to octadecanedioic acid via lysine linker incorporating carboxylated moiety), PheCl₂: (3,4-dichlor)phenylalanine, PheNO₂: (4-nitro)phenylalanine, PheF₅: pentafluoro-phenylalanine, 1-Nal, 2-Nal: napthylalanine, Phg: phenylglycine, TTDS: short chain of polyethylene glycol (1,13-diamino-4,7,10-trioxadecan-succinamic acid).