UniProt-P47871 — Glucagon Receptor (GCGR)

[DRAFT — authored 2026-04-19. UniProt entry web-verified via REST flat-file 2026-04-19.]

Entry

UniProt accession: P47871 (entry name GLR_HUMAN)
Alt accession: Q2M3M5
Protein name: Glucagon receptor (GL-R)
Gene: GCGR
Organism: Homo sapiens (Human)
Sequence length: 477 amino acids
Receptor class: G-protein-coupled receptor, class B (secretin-family); 7-transmembrane-helix architecture

Function Summary

GCGR is the primary receptor for glucagon (pancreatic α-cell product), with dominant hepatic expression. Ligand binding triggers Gs-protein coupling (adenylyl cyclase / cAMP) and phosphatidylinositol-calcium second-messenger signaling. Physiological roles:

Liver: stimulates glycogenolysis and gluconeogenesis → raises blood glucose during fasting
Liver: stimulates hepatic lipid oxidation — the rationale for triple-agonist inclusion in retatrutide (glucagon arm drives additional energy expenditure and hepatic fat reduction beyond GLP-1/GIP)
Extrahepatic effects: direct effects on lipolysis, thermogenesis (brown/beige adipose), and CNS energy expenditure (smaller than hepatic effects)

Features 4 N-linked glycosylation sites, multiple disulfide bonds stabilizing the extracellular domain, rapid internalization following ligand binding. Mutations associated with Mahvash disease (autosomal recessive islet α-cell hyperplasia and pancreatic neuroendocrine tumors from receptor loss-of-function).

Relevance to Module 5 Peptides

Retatrutide: GCGR arm of triple GIP/GLP-1/glucagon agonism — this is the mechanistic distinction from tirzepatide. The glucagon-receptor component is believed to drive the additional weight-loss and hepatic-fat-reduction magnitude observed in Phase 2 data.
Survodutide: GLP-1/glucagon dual agonist (different pipeline agent, same class of GCGR co-targeting)
Semaglutide, Liraglutide, Tirzepatide, CagriSema, Orforglipron: NO GCGR component — included here for teaching contrast

Cross-References to Vault Research Notes

PMID-37366315 – Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A — Phase 2 obesity (Jastreboff 2023)
PMID-37385280 – Retatrutide Phase 2 Trial in Type 2 Diabetes — Phase 2 T2D (Rosenstock 2023)
PMID-38858523 – Retatrutide for MASLD Phase 2a Trial — Phase 2a MASLD (Sanyal 2024)
PMID-38847460 – Survodutide Phase 2 MASH and Fibrosis Trial — survodutide Phase 2 MASH
UniProt-P43220 – GLP1R GLP-1 Receptor — co-target
UniProt-P48546 – GIPR GIP Receptor — co-target

Orchestrator Notes

Primary mechanism reference for Retatrutide profile Mechanism section — specifically the third-arm glucagon component.
Verified 2026-04-19 via UniProt REST flat-file API (https://rest.uniprot.org/uniprotkb/P47871.txt).