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Definition

Gastrin releasing peptide (GRP) is a 27-amino acid linear neuropeptide, structurally and functionally related to bombesin (BB) that mediates neural release of antral gastrin, causes bronchoconstriction and respiratory tract vasodilation, stimulates growth and mitogenesis of cells in culture, and may act as an excitatory neurotransmitter of enteric interneurons.

 

Related peptides

The GRP gene encodes a member of the bombesin-like family of gastrin-releasing peptides. Its preproprotein, following cleavage of a signal peptide, is further processed to produce either the 27 aa GRP or the 10 aa neuromedin C1.  The GRP and neuromedin B (NMB) are structurally related to BB and exist within the mammalian small intestine. A series of potent GRP antagonists have been developed by modification of the COOH terminus of N-acetyl-GRP-20-27. The most potent member of this series, N-acetyl-GRP-20-26-0CH2CH3, obtained by modification of the COOH-terminal region of this peptide blocks GRP-stimulated mitogenesis, inhibits GRP-dependent release of gastrin and blocks GRP-induced elevation of [Ca2+]i in vitro2.

 

Discovery

Bombesin is a peptide originally extracted from the skin of the European discoglossid frog Bombina bombino and possessed profound biological potency in mammals. This led to the discovery of the "mammalian bombesins" GRP5 and NMB3. McDonald TJ et al., in 1978 discovered GRP in extracts from porcine non-antral gastric tissue4.

 

Structural characteristics

Human GRP (hGRP) mRNA encodes a precursor of 148 amino acids containing a typical signal sequence, hGRP consisting of 27 or 28 amino acids, and a carboxyl-terminal extension peptide. hGRP is flanked at its carboxyl terminus by two basic amino acids, following a glycine used for amidation of the carboxyl-terminal methionine. hGRP contains two potential internal tryptic cleavage sites that could generate hGRP-(14-27) or hGRP-(18-27). The two forms of hGRP probably derive from alternative proteolytic processing of pre-proGRP into both GRP-(1-27) and a smaller GRP-like peptide5. While the residues 20-27 of GRP influence binding of the parent peptide to its receptor, the COOH-terminal amino acid is primarily responsible for triggering the subsequent biological response5.

 

Mode of Action

The effects of GRP are mediated through the GRP receptor. This receptor is a glycosylated, 7-transmembrane G-protein coupled receptor that activates the phospholipase C signaling pathway. The receptor is aberrantly expressed in numerous cancers such as those of the lung, colon, and prostate6.

 

Functions

GRP is released by the post-ganglionic fibres of the vagus nerve, which innervate the G cells of the stomach and stimulate them to release gastrin. GRP can directly stimulate pepsinogen release from chief cells by a specific GRP receptor that mobilizes intracellular calcium. GRP has a prominent role as a tumor marker in the diagnosis of small-cell lung carcinoma. It regulates numerous functions of the gastrointestinal and central nervous systems, including smooth muscle cell contraction, and epithelial cell proliferation and is a potent mitogen for neoplastic tissues6.

 

References

 

1.     Chandan R, Newell SM, Brown DR (1988).Actions of gastrin-releasing peptide and related mammalian and amphibian peptides on ion transport in the porcine proximal jejunum. Regul Pept, 23(1):1-14.

2.     Heimbrook DC, Saari WS, Balishin NL, Friedman A, Moore KS, Reimen MW, Kiefer DM, Rotberg NS, Wallen JW, Oliff A(1989). Carboxyl-terminal Modification of a Gastrin Releasing Peptide Derivative Generates Potent Antagonists. J Biol Chem, 264(19):11258-11262.

3.     Preston SR, Woodhouse LF, Jones-Blackett S, Wyatt JI, Primrose JN(1993). Shaun R. Preston, Linda F. Woodhouse, Steven Jones-Blackett, Judy I. Wyatt, and John N. Primrose.1993. High Affinity Binding Sites for Gastrin Releasing Peptide on Human Gastric Cancer and Menetrier's Mucosa. Cancer Res, 53(21):5090-5092.

4.     McDonald TJ, Nilsson G, Vagne M, Ghatei M, Bloom SR, Mutt V.1978. A gastrin releasing peptide from the porcine nonantral gastric tissue. Gut, 19(9):767-774.

5.     Spindel ER, Chin WW, Price J, Rees LH, Besser GM, Habener JF(1984). Cloning and characterization of cDNAs encoding human gastrin-releasing peptide. Proc. Nati. Acad. Sci. USA 81(18):5699-5703.

6.     Martínez A, Zudaire E, Julián M, Moody TW, Cuttitta F (2005). Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo. Oncogene, 24(25):4106-4113.

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