Gastrin-34: natural stomach-acid hormone (Big Gastrin)
A gut hormone made after meals that tells the stomach to produce acid and signals fullness to the brain; a natural body chemical, not a drug.
- Class
- Endogenous gastrointestinal peptide hormone
- Status
- No approved therapeutic status identified in source
- Best-supported effect
- Gastric acid secretion and parietal-cell stimulation via CCK2/gastrin receptor — endogenous physiological role only; no exogenous therapeutic evidence attached
- Main caveat
- This card describes an endogenous hormone with known physiology; no clinical, animal-model, or in vitro evidence for exogenous therapeutic use is attached to the source
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Gastrin-34 — also called Big Gastrin or G-34 — is a 34-amino-acid gut hormone and the larger of the two principal circulating forms of gastrin. It is produced in the G cells of the gastric antrum and duodenal mucosa as part of the body's normal machinery for regulating stomach acid after a meal. Despite being secreted in smaller quantities than its shorter sibling gastrin-17 (G-17), G-34 persists far longer in the bloodstream and accounts for most of the gastrin detectable in fasting serum. The sequence shown here represents the backbone of the mature peptide; the biologically active form carries a C-terminal amide cap (the conserved …Trp-Met-Asp-Phe-NH₂ pentapeptide shared by all active gastrins) and, in approximately half the natural molecules, a sulfated tyrosine residue — neither modification is visible in the stored single-letter sequence (Zeng and colleagues 2020; Boel and colleagues 1983).
History
The gastrin story begins at the University of Liverpool, where Hilda Tracy and Roderic Alfred Gregory isolated the hormone from human gastric antral mucosa in 1964, publishing the structures of two 17-residue peptides — gastrin I (unsulfated) and gastrin II (sulfated at tyrosine) — in a landmark set of three back-to-back Nature papers. They subsequently characterised a larger, less acidic set of peptides that were simply G-17 extended at their N-terminus by 17 additional residues; these were named "big gastrin" and are now universally called G-34. The molecular basis of gastrin's diversity was resolved in 1983 when Boel and colleagues cloned the human gastrin cDNA from a pancreatic gastrinoma, establishing that the preprogastrin precursor (101 amino acids) encodes both G-17 and G-34 as products of differential prohormone processing (Boel and colleagues 1983). Prohormone convertases PC1/3 and PC2 cleave progastrin at specific dibasic sites to generate G-34 and then G-17 sequentially, with C-terminal amidation added as the final activation step.
What it does
G-34's primary job is to stimulate gastric acid secretion — the same role as G-17, only with a slower onset and more sustained action due to its longer half-life. After a meal, the antrum releases predominantly G-17; during fasting, G-34 predominates in circulation because its plasma half-life (~15–40 minutes, compared to ~3–8 minutes for G-17) means it clears much more slowly (Zeng and colleagues 2020). Equimolar doses of G-34 and G-17 produce roughly comparable acid outputs, though G-17 is more potent on a per-unit-serum-concentration basis because far less of it is needed to achieve the same peak level.
Beyond acid secretion, gastrin-34 (like all amidated gastrins) exerts trophic, or growth-promoting, effects on the gastric mucosa — most prominently on the enterochromaffin-like (ECL) cells that sit alongside the acid-secreting parietal cells. Chronic elevation of gastrin drives ECL cell proliferation, and at sustained high levels can lead to ECL cell hyperplasia and, eventually, neoplastic change (Zeng and colleagues 2020).
Evidence
- Human: G-34 is measured in clinical practice as part of serum gastrin assays used to diagnose hypersecretory disorders. Zollinger-Ellison syndrome — caused by gastrin-secreting pancreatic or duodenal tumors — involves dramatic elevations in circulating gastrin that include the G-34 fraction. Radiolabeled gastrin analogs targeting the CCK2 receptor (which G-34 activates) have been evaluated in clinical imaging studies of medullary thyroid carcinoma and other CCK2R-overexpressing tumors, with 111In-labeled minigastrin (MG0) visualising lesions in patients with occult medullary thyroid carcinoma (Roosenburg and colleagues 2011).
- Animal: Early characterisation studies in dogs established G-34's acid-stimulating action and disappearance half-time. Gastrin receptor knockout mouse models have confirmed the CCK2R as the principal mediator of gastrin-driven acid secretion.
- In vitro: CCK2R expressed on ECL and parietal cells mediates G-34's signalling through a Gq/PLC/Ca²⁺/PKC cascade. Trophic signalling through CCK2R activates the EGFR, PI3K, and ERK/MAPK pathways in ECL cell lines (Zeng and colleagues 2020; Berna and colleagues 2007).
Known effects
- Gastric acid stimulation — Physiological; mediated via CCK2R on ECL cells (histamine release → H2R on parietal cells) and directly on parietal cells
- ECL cell proliferation (trophic) — Established in animal models and inferred from human hypergastrinemia data; chronic hypergastrinemia → ECL hyperplasia
- Sustained fasting acid tone — G-34's long half-life makes it the principal interdigestive gastrin in human serum
- Calcitonin release from medullary thyroid carcinoma cells — CCK2R activation in MTC cells stimulates calcitonin secretion and calcitonin gene transcription; basis for radiopeptide imaging
- Tumour receptor targeting — CCK2R overexpression in >90% of medullary thyroid carcinomas and 89% of small cell lung cancers has been exploited in radiolabelled gastrin analog imaging (Roosenburg and colleagues 2011)
Safety signals
Gastrin-34 is an endogenous human hormone; exogenous administration has been used experimentally but it is not an approved therapeutic. Pathological hypergastrinemia (as in Zollinger-Ellison syndrome) causes peptic ulceration, diarrhoea, and, over time, ECL cell hyperplasia. Long-term pharmacological suppression of gastric acid with proton-pump inhibitors raises endogenous gastrin levels (including G-34) as a reflexive compensatory response; the clinical significance of this chronic mild hypergastrinemia in terms of gastric neoplasia risk remains under investigation.
Regulatory status
- US / EU: Not approved as a drug; used as a research reagent and as a reference standard in gastrin immunoassays.
- WADA: Not listed as a prohibited substance.
Mechanism
CCK2R (also called the gastrin receptor or CCK-B receptor; gene CCKBR) is the principal receptor for G-34. It is a class A GPCR that couples through Gq protein to activate phospholipase Cβ, generating diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 drives cytosolic Ca²⁺ release; the combined Ca²⁺ and DAG signal activates protein kinase C, which together with downstream MAPK (ERK1/2) activation mediates both the acute secretory and the chronic trophic responses (Zeng and colleagues 2020; Miller and colleagues 2008).
The primary effector cell for acid secretion is the ECL cell: CCK2R stimulation triggers histamine exocytosis, and histamine then acts on H2 receptors on neighbouring parietal cells to activate adenylyl cyclase and drive H⁺/K⁺-ATPase-mediated proton secretion. G-34 can also activate CCK2R directly on parietal cells, providing a parallel, histamine-independent acid signal. Trophic signalling additionally recruits the EGFR transactivation pathway and PI3K/Akt axis, accounting for the proliferative effects on ECL cells (Zeng and colleagues 2020).
The stored sequence (LGPQGPPHLVADPSKKQGPWLEEEEEAYGWMDF) represents the 34-residue backbone. The biologically active molecule carries a C-terminal amide (–Phe-NH₂) critical for receptor engagement, and approximately half of naturally occurring G-34 molecules are sulfated at the tyrosine residue near the C-terminus (Tyr on gastrin II variants); sulfation modestly enhances CCK2R binding affinity but is not required for activity (Berna and colleagues 2007). The card's target annotation lists the CCK-A receptor (cckar); the primary pharmacological target of gastrin-34 in published literature is the CCK-B/gastrin receptor (CCK2R / CCKBR), which has markedly higher affinity for gastrin than CCK-A (Miller and colleagues 2008).
Related peptides
- Gastrin-17 — the more abundant postprandial form; shares the C-terminal sequence and CCK2R binding pharmacophore with G-34 but clears ~5× faster
- Cholecystokinin (CCK) — the evolutionary sibling hormone; shares the C-terminal –Trp-Met-Asp-Phe-NH₂ motif and activates both CCK1R and CCK2R, with CCK1R preference distinguishing it from gastrin; see also related CCK receptor pharmacology literature (Berna and colleagues 2007; Miller and colleagues 2008)
- Minigastrin (MG0/MG11) — synthetic truncated gastrin analogs developed for radiolabelled CCK2R imaging of medullary thyroid carcinoma and other neuroendocrine tumors (Roosenburg and colleagues 2011)
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Is gastrin-34 actually binding to its natural gastrin receptor rather than the cholecystokinin receptor it is annotated as targeting?
If the receptor annotation is wrong, clinical trials targeting CCK-AR with gastrin-34 as a reference compound would give misleading data. Correcting the target label protects the validity of research in stomach acid disorders and GI cancers.
Is gastrin-34 just a slow-release version of gastrin-17, gradually trimmed down by blood enzymes over hours?
If gastrin-34 is a natural depot form, it changes how doctors should interpret gastrin blood tests and could inspire engineered peptide drugs with built-in slow-release properties for sustained acid regulation or beta-cell therapies, without needing chemical modifications.
Does the long chain of negatively charged amino acids in gastrin-34 help it find its target cells faster by sticking near positively charged cell surfaces?
If this pre-concentration mechanism is real, it explains why the larger gastrin-34 is more potent in the stomach than its shorter cousin despite similar receptor binding, and could inspire the design of longer-acting gastrin analogues for conditions requiring precise acid regulation.
Could gastrin-34's longer stay in the bloodstream make it more effective than gastrin-17 at driving the growth of insulin-producing pancreatic cells?
Restoring insulin-producing cells is a goal for both type 1 and advanced type 2 diabetes. A naturally longer-lasting gastrin form that stays in the blood longer might regenerate more beta cells per dose, improving on current experimental approaches that use the shorter form.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.6045112609863281 | boltz-2 |
| ranking score | 0.6949019432067871 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.376 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10616,
sequence = {LGPQGPPHLVADPSKKQGPWLEEEEEAYGWMDF},
target = {cckar},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}