Prolactin Releasing Peptides、催乳素釋放肽

Definition

Prolactin (PRL) is involved in the development of the mammary glands and the promotion of milk synthesis in mammals. Prolactin-releasing peptide (PrRP), expressed specifically in the human pituitary is identified in the hypothalamus as a potent prolactin-releasing factor for anterior pituitary cells.

Discovery

In 2006 Samson et al., originally reported that PrRP act in the anterior lobe of the pituitary gland to stimulate PRL release; however, numerous other pharmacologic actions of PrRP have been described. In the central nervous system PrRP inhibits food intake, stimulates sympathetic tone, and activates stress hormone secretion. There is presence of immunoreactive PrRP in a pheochromocytoma–derived cell line (PC-12) and the ability of exogenous PrRP to stimulate adenylyl cyclase activity in these cultures was studied. Findings suggest that PrRP stimulated PC-12 cell growth 1.  Maruyama M et al., in 2001 examined PrRP as a novel stress mediator in the central nervous system and studied the effect of water immersion-restraint stress on c-Fos protein accumulation in PrRP- and TH-immunoreactive neurons 2.

Structural Characteristics

Boyle RG et al., in 2004 studied the structure-activity studies on PrRP, analogues of PrRP-(19-31)-peptide. They carried out a series of single replacement analogues of PrRP-(19-31)-peptide has shown that good functional activity was retained when Phe31 was replaced with His(Bzl), Phe(4Cl), Nle, Trp, Cys(Bzl) or Glu(OBzl); when Val28 or Ile25 was replaced with Phg; when Gly24 was replaced with D-Ala, L-Ala, Pro or Sar; when Ser22 was replaced with Gly and when Ala21 was replaced with Thr or MeAla. The results confirm that the functionally important residues are located within the carboxyl terminal segment, -Ile-Arg-Pro-Val-Gly-Arg-Phe-NH2 3.

Mode of Action

Hypothalamic peptide hormones regulate the secretion of most of the anterior pituitary hormones, that is, growth hormone, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone and adrenocorticotropin. These peptides do not regulate the secretion of prolactin, at least in a specific manner, however. The peptides act through specific receptors, which are referred to as seven-transmembrane-domain receptors or G-protein-coupled receptors. Although prolactin is important in pregnancy and lactation in mammals, and is involved in the development of the mammary glands and the promotion of milk synthesis, a specific prolactin-releasing hormone has remained unknown. Hinuma et al., identified a potent candidate for such a hormone. They first proposed that there may still be unknown peptide hormone factors that control pituitary function through seven-transmembrane-domain receptors. They isolated the complementary DNA encoding an 'orphan' receptor (that is, one for which the ligand is unknown). This receptor, hGR3, is specifically expressed in the human pituitary. They searched for the hGR3 ligand in the hypothalamus and identified a new peptide, which shares no sequence similarity with known peptides and proteins, as an endogenous ligand. They showed that this ligand is a potent prolactin-releasing factor for rat anterior pituitary cells 4. The PRL-releasing activity of the novel PrRPs was studied in vivo using male and lactating female rats. Whereas thyrotropin-releasing hormone effectively stimulated PRL and thyrotropin release as expected, PrRP in both animal models neither stimulated PRL secretion nor affected the release of other pituitary hormones. At the anterior pituitary level, in situ hybridization (ISH) histochemistry and Northern blot analysis revealed significantly higher expression levels of PrRP receptor (UHR-1) transcripts in female compared to male rats but not between lactating and nonlactating animals. By ISH, expression of UHR-1 mRNA was also detected in the intermediate lobe but not in the posterior pituitary. UHR-1 transcripts were also readily detectable in various hypothalamic brain areas whereas expression of PrRP mRNA was restricted to the ventral part of the dorsomedial hypothalamic nucleus but was not detected in neuroendocrine hypothalamic nuclei (e.g. PVN, SON). Authors assumed that in the central nervous system, PrRP may likely have functions as a neuromodulator 5.

Functions

Control of food intake, PrRP peptide may play a role in the control of food intake, stress response and nociception. PrRP is a member of the RFamide peptide family and is an endogenous ligand for the orphan G protein-coupled receptor (GPCR), hGR3.Furthermore, a role for endogenous PrRP in PC-12 cell growth is suggested by the observations that antisense oligonucleotides and small interfering RNA molecules, which decrease peptide content in these cells, also decrease thymidine incorporation, suggesting an autocrine action of the peptide 1.   .

Stimulate PRL, PrRP is known to stimulate PRL release both in vitro and in vivo 6. It has been demonstrated that PrRP-producing cells exist in the dorsomedial hypothalamic nucleus (DM) and in the A1 region of the ventrolateral reticular formation and the A2 region of the nucleus of the solitary tract in medulla oblongata 7.

Role in the neuroendocrine system, these PrRPproducing neurons extend their axons to magno- and parvocellular neurosecretory cells in the paraventricular hypothalamic nucleus (PVH) and then make synapse-like contact with these cell bodies, in which PrRP receptors are known to exist. These morphological data strongly suggest that PrRP plays an important biological role in the neuroendocrine system 8.

References

1.Samson WK, Taylor MM (2006). Prolactin releasing peptide (PrRP): An endogenous regulator of cell growth. Peptides, 27(5):1099-1103.

2.Maruyama M, Matsumoto H, Fujiwara K, Noguchi J, Kitada C, Fujino M, Inoue K (2001).  Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology. 42(5):2032-2038.

3.Boyle RG, Downham R, Ganguly T, Humphries J, Smith J, Travers S (2004). Structure-activity studies on prolactin-releasing peptide (PrRP). Analogues of PrRP-(19-31)-peptide. J Pept Sci., 11(3):161-165.

4.Hinuma S, Habata Y, Fujii R, Kawamata Y, Hosoya M, Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H, Sekiguchi M, Kurokawa T, Nishimura O, Onda H, Fujino M(1998). A prolactin-releasing peptide in the brain. Nature, 393(6682):272-276.

5.Jarry H, Heuer H, Schomburg L, Bauer K (2000). Prolactin-Releasing peptides do not stimulate prolactin release in vivo. Neuroendocrinology, 71(4):262-267.

6.Matsumoto H, Noguchi J, Horikoshi Y, Kawamata Y, Kitada C, Hinuma S, Onda H, Nishimura O, Fujino M (1999). Stimulation of prolactin release by prolactin-releasing peptide in rats. Biochem Biophys Res Commun., 259(2):321-324.

7.Maruyama M, Matsumoto H, Fujiwara K, Kitada C, Hinuma S, Onda H, Fujino M, Inoue K (1999). Immunocytochemical localization of prolactin releasing peptide in the rat brain. Endocrinology, 140(5):2326-2333.

8.Matsumoto H, Maruyama M, Noguchi J, Horikoshi Y, Fujiwara K, Kitada C, Hinuma S, Onda H, Nishimura O, Inoue K, Fujino M (2000). Stimulation of corticotropin-releasing hormone-mediated adrenocorticotropin secretion by central administration of prolactin-releasing peptide in rats. Neurosci Lett., 285(3):234-238.