Gut satiety peptide fragment: GRP[5-27]

What this is

Gastrin releasing peptide [5-27] (GRP[5-27]) is a 23-amino-acid peptide fragment belonging to the bombesin family of gut neuropeptides. It was first isolated from dog intestinal tissue in 1983 and represents the middle-length form of the three canine gastrin-releasing peptide variants characterised by Reeve and colleagues (Reeve et al., J Biol Chem, 1983). The stored sequence (GGQGTVLDKMYPRGNHWAVGHLM) corresponds to residues 5–27 of the full-length 27-residue GRP; the peptide carries a C-terminal amide (–NH₂) that is not encoded in the raw one-letter sequence. Functionally, GRP family peptides stimulate gastrin release from gastric G cells and reduce food intake — effects that intersect with the cholecystokinin (CCK) / CCKAR axis in the gut.

History

Three forms of GRP were identified in canine intestinal extracts and their amino acid sequences were determined by Reeve and colleagues in 1983 (Journal of Biological Chemistry, doi: 10.1016/s0021-9258(20)81930-9): a 27-residue peptide, a 23-residue form (GRP[5-27], this card), and a 10-residue C-terminal fragment. These peptides were recognised as the mammalian homologues of bombesin, a 14-amino-acid peptide previously isolated in the early 1970s from the skin of the European fire-bellied toad (Bombina bombina). The 23-mer form begins where the 27-mer's four-residue N-terminal extension (Ala-Pro-Val-Pro) ends, making GRP[5-27] the dominant intestinal fragment — a natural processing product of the GRP precursor. The cholecystokinin A receptor (CCKAR) was structurally characterised in detail by Miller and colleagues (Pharmacology & Therapeutics, 2008, doi: 10.1016/j.pharmthera.2008.05.001), establishing the molecular framework within which GRP-family/CCK pathway interactions are studied.

What it does

GRP[5-27] belongs to the bombesin family of peptides, which in mammals reduce food intake (satiety signalling), stimulate gastrin release from stomach G cells, increase gastric acid secretion, and regulate gastrointestinal motility. GRP-family peptides can also trigger gallbladder contraction indirectly by promoting CCK release — CCK then acts on CCKAR on gallbladder smooth muscle to drive emptying (Zeng et al., Frontiers in Endocrinology, 2020, doi: 10.3389/fendo.2020.00112). The receptor most directly engaged by GRP-family ligands is GRPR (the GRP receptor, also called BB2), a Gq-coupled GPCR that shares approximately 27% sequence identity with CCKAR (Miller et al., 2008). CCKAR itself is a well-characterised gut satiety receptor: it mediates CCK-driven gallbladder contraction, pancreatic enzyme secretion, and vagal satiety signalling (Wang et al., Genes, 2020, doi: 10.3390/genes11121438; Zeng et al., 2020). GRP[5-27] thus serves as a pharmacological probe for dissecting the bombesin/GRP axis and its crosstalk with the CCK/CCKAR system.

Evidence

• Human: No human clinical trials for GRP[5-27] specifically. Human GRP-27 infusion studies have examined effects on gastrointestinal hormone release; no registered trials on ClinicalTrials.gov for the GRP[5-27] fragment.
• Animal: GRP[5-27] was isolated and sequenced from canine intestinal extracts and was shown to be one of three molecular forms of canine gastrin-releasing peptide that all stimulated gastrin release from isolated canine G cells in a dose-dependent manner (Reeve et al., 1983). Intravenous infusion studies in rats with the full-length GRP-27 demonstrated selective reduction in meal size.
• In vitro: GRP-family peptides activate Gq-coupled signalling cascades (phospholipase C, intracellular calcium mobilisation, PKC activation) through GRPR in cell-based assays.

Known effects

• Gastrin release stimulation — Demonstrated in canine G-cell primary culture (Reeve et al., 1983)
• Satiety / food intake reduction — Established for the GRP/bombesin family in mammals; mechanistic (GRP-family receptor-mediated)
• Gastrointestinal motility regulation — Preclinical; GRP-family peptides affect smooth muscle and enteric neuron activity
• Indirect gallbladder contraction — Via CCK release acting on CCKAR (Zeng et al., 2020)

Mechanism

GRP[5-27] belongs to the bombesin family of neuropeptides, which act primarily through GRPR (BB2 receptor), a class A GPCR that couples to Gq proteins. Gq activation triggers phospholipase C, mobilisation of intracellular calcium, and activation of protein kinase C — the same downstream pathway used by CCKAR, which is structurally related (Miller et al., 2008). The C-terminal segment of GRP peptides (roughly residues 19-27 of GRP-27) forms the receptor-binding "message" that inserts into the transmembrane helical bundle, while the N-terminal region provides additional receptor-contact ("address") interactions. The two shorter canine forms — GRP[5-27] (this card) and GRP[18-27] — retain this C-terminal pharmacophore. CCKAR is the cognate receptor for CCK, requiring the sulfated heptapeptide-amide C-terminus of CCK for high-affinity binding; it is expressed predominantly in gallbladder smooth muscle and small intestinal epithelium, where it drives gallbladder emptying, pancreatic enzyme secretion, and intestinal transit (Wang et al., 2020; Zeng et al., 2020). The CCKAR gene (Lith13) has been identified as a gallstone susceptibility gene in mice: knockout impairs gallbladder contraction, promotes cholesterol crystallisation, and increases intestinal cholesterol absorption (Wang et al., 2020). GRP[5-27] is used as a research tool to probe GRPR-mediated signalling and to map the functional overlap between the GRP/bombesin and CCK/CCKAR systems in gut physiology.

Related peptides

• Cholecystokinin (CCK) — The endogenous ligand of CCKAR; a gut hormone released postprandially that drives gallbladder contraction, pancreatic secretion, and satiety via vagal afferents (see also Mutt and colleagues on CCK structure, European Journal of Biochemistry, 1968, doi: 10.1111/j.1432-1033.1968.tb00433.x).
• Bombesin — The amphibian 14-residue prototype of the GRP family, originally isolated from Bombina bombina skin; the pharmacological anchor used in structure–activity studies of GRPR ligands.
• Neuromedin C (GRP[18-27]) — The 10-residue C-terminal fragment of canine GRP, also identified by Reeve et al. (1983) from the same extracts; contains the minimal receptor-binding core.