What Is Gastrin-Releasing Peptide (GRP)?

Peptide biology

Gastrin-releasing peptide is one of the worst-named molecules in endocrinology. It was pulled out of a pig stomach in 1978, named for the first thing anyone saw it do, and has since turned out to be the spinal cord’s dedicated itch signal, a light-input messenger for the body clock, a brake on fear memory, and a receptor target oncology has been chasing for thirty years. It is not a form of gastrin, is not related to gastrin, and does not act on gastrin’s receptor.

From toad skin to pig stomach

The story starts with amphibians. In 1971 Anastasi, Erspamer and Bucci reported the isolation and structure of two analogous active peptides from the skin of European amphibians — bombesin from Bombina, the fire-bellied toads, and alytesin from Alytes, the midwife toads. A follow-up paper the next year laid out the amino-acid sequences: bombesin is a 14-residue peptide, a tetradecapeptide, with an amidated C-terminus.

Bombesin did surprising things to mammals, which set off a search for a mammalian equivalent. McDonald, Mutt and colleagues found it in porcine non-antral gastric tissue, reporting the isolation in Gut in 1978 and the characterisation in Biochemical and Biophysical Research Communications in 1979. The peptide they described was 27 residues long, and they named it for its most conspicuous action — it released gastrin.

What gastrin-releasing peptide is, molecularly

The human gene GRP sits at 18q21.32 and encodes a 148-amino-acid precursor, preproGRP (UniProt P07492). A 23-residue signal peptide comes off the front. Residues 24 to 50 are the mature 27-residue peptide:

VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH₂

The last ten residues of that — GNHWAVGHLM-NH₂ — are themselves a separately annotated bioactive peptide, neuromedin C, also called GRP-10 or GRP(18–27). The final residue carries a single recorded modification: methionine amide. That C-terminal amide is installed by peptidylglycine alpha-amidating monooxygenase, the only enzyme known to do the job, and for amidated peptides generally the uncapped version retains only a fraction of a percent of its activity. It is the smallest possible edit in a 148-residue precursor, and it decides whether the product works.

The C-terminus is also where the amphibian connection lives. Bombesin ends Trp-Ala-Val-Gly-His-Leu-Met-NH₂; so does human GRP. The heptapeptide is identical and the decapeptides differ at a single position. That is why a frog-skin peptide activates human receptors at all, and why bombesin analogues remain the scaffold for GRPR-targeted chemistry.

The rest of the precursor is not waste. Residues 54 to 148 form a C-terminal propeptide — the fragment clinical laboratories measure as ProGRP, because it is far more stable in circulation than the mature peptide.

The name is misleading, and worth unpicking

GRP does release gastrin. UniProt’s functional annotation says so directly: it stimulates gastrin release as well as other gastrointestinal hormones. But the mechanism is indirect. Efferent vagal fibres running in the gastric myenteric plexus release GRP from enteric neurons that innervate antral G cells; GRP acting on those G cells triggers gastrin secretion; gastrin then drives histamine release from enterochromaffin-like cells and acid from parietal cells, with somatostatin from D cells providing the paracrine brake. GRP is a neurotransmitter in the circuit that switches gastrin on — not a hormone acting on the acid-secreting cell.

Beyond that single functional link, the two molecules have nothing in common: different chromosomes, different precursors, different families, different receptors, different C-terminal pharmacophores.

Three receptors, two of them on the X chromosome

Mammals have three bombesin receptors, all G-protein-coupled receptors signalling through phospholipase C:

• BB2 (GRPR) — the receptor for GRP. Gene GRPR at Xp22.2. NCBI describes it as a glycosylated seven-transmembrane GPCR that activates the phospholipase C pathway, and notes it is aberrantly expressed in numerous cancers including lung, colon and prostate.
• BB1 (NMBR) — the receptor preferring neuromedin B, GRP’s closest mammalian relative.
• BB3 (BRS3) — at Xq26.3, and still an orphan. The 1997 paper that produced the knockout mouse said plainly that determining its function had been difficult because of its low affinity for bombesin and its lack of an identified natural ligand. Nearly three decades later that remains true.

The BRS-3 knockout is worth knowing about on its own: those mice developed mild obesity with hypertension and impaired glucose metabolism, reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia. A receptor nobody can name a ligand for turns out to sit on energy balance.

The itch pathway

The result that made GRP famous outside gastroenterology came in 2007. Sun and Chen reported in Nature that GRP is expressed in a small subset of peptidergic dorsal root ganglion neurons while its receptor is restricted to lamina I of the dorsal spinal cord. GRPR mutant mice showed comparable thermal, mechanical, inflammatory and neuropathic pain responses to wild-type animals — but markedly reduced scratching in response to itch-provoking stimuli, and a GRPR antagonist delivered into the spinal cerebrospinal fluid inhibited scratching in three independent itch models.

Two years later the same group went further, selectively ablating the GRPR-expressing lamina I neurons themselves. Those mice showed profound scratching deficits to every pruritogen tested, histamine-dependent or not, while pain behaviours were completely unaffected. That is about as clean a demonstration of a labelled line as sensory neuroscience produces, and it undercut the long-standing teaching that itch is simply low-intensity pain.

The honest caveat is that this is all rodent work, and half of it is still argued about. A 2020 Nature Communications paper opens by stating that GRP functions as a neurotransmitter for non-histaminergic itch but that its site of action — sensory neurons versus spinal cord — remains controversial, and reports that conditional knockout of Grp in sensory neurons attenuates non-histaminergic itch while genetic ablation of spinal Grp neurons does not affect itch or pain transmission. The receptor side of the story is settled; the ligand’s origin is not.

What else it does

• Fear memory. GRP is highly expressed in the lateral amygdala and in the pathways carrying auditory fear information to it, where GRPR sits on GABAergic interneurons. UniProt summarises the finding directly: GRP operates as negative feedback regulating fear, linking GRPR expression, long-term potentiation and amygdala-dependent fear memory. GRPR-deficient mice show enhanced long-term potentiation and greater, more persistent fear memory.
• Satiety. Bombesin and GRP reduce meal size in rats, and the feeding-suppression effect of bombesin is lost in GRPR-deficient mice. GRP belongs to the same short-term meal-termination signalling as cholecystokinin.
• The body clock. GRP is made by light-responsive neurons in the ventral core of the suprachiasmatic nucleus, and applying it phase-shifts circadian rhythms via CREB and Per1. A 2025 study added the nuance that removing GRP or ablating SCN GRP neurons does not abolish photic entrainment — the network is redundant.
• Gut and airway. NCBI’s gene summary lists release of gastrointestinal hormones, smooth-muscle contraction and epithelial cell proliferation. Bombesin-like peptides from pulmonary neuroendocrine cells participate in fetal lung development, and elevated urinary bombesin-like peptide has been reported to precede clinical bronchopulmonary dysplasia in very preterm infants.
• Thermoregulation. Central bombesin lowers core temperature in rats, an effect reported by Brown, Rivier and Vale in Science in 1977, seen in cold-exposed rather than thermoneutral animals.

ProGRP, cancer and imaging

GRPR is over-expressed in several tumour types, and the numbers are substantial. In 1,432 primary invasive breast cancers, GRPR expression was moderate or strong in 1,085 tumours — 75.8 percent — with oestrogen-receptor positivity the strongest predictor. Immunohistochemistry across 238 lung cancer samples found GRPR in 52.6 percent of small cell and 62.5 percent of non-small cell cases. In prostate, receptor autoradiography going back to the 1990s found GRPR abundant in neoplastic tissue and rare, or present only at low density, in benign hyperplasia and normal prostate.

That expression pattern has been exploited in two ways. ProGRP, the stable C-terminal propeptide, is used as a serum or plasma biomarker for small cell lung cancer; a meta-analysis across 5,146 patients found pooled sensitivity of about 0.72 and specificity of about 0.92. Commercial assays are marketed in Europe and Japan.

Separately, GRPR is a target for radiolabelled peptides, in the same way somatostatin receptor 2 is targeted in peptide receptor radionuclide therapy. GRPR-directed antagonists built on bombesin scaffolds have been licensed to several companies, and clinical work is ongoing. The largest study so far — a single-centre phase 2/3 imaging trial in 100 men with biochemically recurrent prostate cancer and non-contributory conventional imaging — found a gallium-68 GRPR ligand combined with MRI positive in 69 patients versus 40 for MRI alone, detecting 143 lesions versus 96, with no grade 1 or higher adverse events. In a head-to-head comparison in metastatic castration-resistant disease, however, a PSMA tracer identified 23 percent more lesions than the GRPR tracer — though GRPR agents have minimal hepatobiliary clearance, an advantage for small liver and mesenteric lesions.

What is not established

Frequently asked questions

Is gastrin-releasing peptide the same as bombesin?

No. Bombesin is an amphibian peptide 14 residues long; GRP is its 27-residue mammalian counterpart. They are family members, not the same molecule. What they share is the C-terminal heptapeptide that does the receptor binding, which is why bombesin works on mammalian receptors and why bombesin analogues are still used as GRPR-targeting scaffolds.

Why is it named after gastrin if it mostly does other things?

Because it was named in 1978 for the assay that found it. Gastrin release was the readout in the pig-stomach preparation where the peptide was isolated, and the name stuck long before the itch, circadian, fear and oncology literature existed.

What is ProGRP, and why measure it instead of GRP?

ProGRP is the C-terminal propeptide, residues 54 to 148 of the precursor, left over after the active peptide is cut out. It is far more stable in circulation than mature GRP, which makes it the practical thing to assay. It is used as a small cell lung cancer biomarker, with assays marketed in Europe and Japan.

Does blocking GRPR stop itching in people?

That has not been demonstrated. The antagonist experiments that abolished scratching were done in mice, by injection into spinal cerebrospinal fluid or by destroying spinal neurons. Translating that into a human anti-itch drug is an open research question, not an available option.

References

1. Anastasi A, Erspamer V, Bucci M. Isolation and structure of bombesin and alytesin, two analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 1971;27:166–167. PMID 5544731
2. McDonald TJ, Jörnvall H, Nilsson G, et al. Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun 1979;90:227–233. PMID 496973
3. UniProt P07492 — GRP_HUMAN, gastrin-releasing peptide precursor. UniProtKB
4. Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007;448:700–703. Nature
5. Sun YG, Zhao ZQ, Meng XL, et al. Cellular basis of itch sensation. Science 2009;325:1531–1534. Science
6. Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology LXVIII: mammalian bombesin receptors. Pharmacol Rev 2008;60:1–42. PMC2517428
7. Barry DM, et al. Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors. Nat Commun 2020;11:1397. Nature Communications
8. Ohki-Hamazaki H, et al. Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity. Nature 1997;390:165–169. Nature
9. Morgat C, et al. Expression of gastrin-releasing peptide receptor in breast cancer: a study of 1,432 primary tumors. J Nucl Med 2017;58:1401. JNM
10. A vision for gastrin-releasing peptide receptor targeting for imaging and therapy. J Nucl Med 2025;66:1160. JNM
11. NCBI Gene 2925 — GRPR, gastrin releasing peptide receptor. NCBI Gene

Informational only — not medical advice. VialHelp does not sell peptides and does not recommend any product, treatment or dose. No gastrin-releasing peptide or GRPR-targeted agent is an approved medicine; all human work described here is investigational and conducted in clinical trials. Discuss any medical question with a qualified healthcare professional. Intended for readers 21+.