What is Glucagon receptor?
Also called: GCGR, GcgR
The class B G protein-coupled receptor for glucagon, acting mainly in the liver; it signals through cAMP and calcium and is the third target of triple agonists such as retatrutide.
By the APL Research Team · Updated
The glucagon receptor (GCGR) is the receptor through which glucagon, the 29-residue hormone of pancreatic α-cells, acts on its targets, above all the liver. When the rat receptor was expression-cloned in 1993 it bound glucagon, raised intracellular cAMP and also increased intracellular calcium, and its sequence placed it beside the calcitonin and parathyroid hormone receptors [1]. It is one of the class B1 peptide-hormone receptors, together with the GLP-1 receptor and GIP receptor.
Structure
The 3.0 Å crystal structure of full-length human GCGR, captured in an inactive state, showed the extracellular domain joined to the transmembrane bundle by a 12-residue "stalk" that forms a β-strand rather than the α-helix seen in an earlier structure of the transmembrane domain alone [2]. The stalk and the first extracellular loop pack into a compact β-sheet, and crosslinking and dynamics experiments pointed to both as regulators of peptide binding and activation [2]. Because the three receptors share this two-domain layout, a peptide designed for one is routinely tested at the other two.
What the receptor controls
| Process | Evidence |
|---|---|
| Fasting glucose | Gcgr-knockout mice ran lower blood glucose throughout the day [3]; receptor antagonists have been used to measure glucagon's contribution to fasting glucose in type 2 diabetes [4] |
| α-cell mass and glucagon output | Knockout mice developed very high glucagon levels with α-cell hyperplasia and a 3- to 10-fold rise in circulating GLP-1 amide [3] |
| Amino acid turnover and ureagenesis | Glucagon drives hepatic amino acid clearance, and amino acids such as alanine in turn stimulate glucagon secretion: the liver–α-cell axis [4] |
| Body composition | Knockout mice had reduced adiposity but normal body weight, food intake and energy expenditure [3] |
The knockout phenotype is a reminder that removing a receptor triggers compensation: the GLP-1 rise in these mice means not every effect can be attributed to absent glucagon signalling.
GCGR in co-agonist research
Glucagon was long a difficult research reagent. A 2017 review notes that analogues stable and soluble in aqueous solution were what opened up modern glucagon pharmacology [5]. The native hormone combines poor solubility, a strong tendency to aggregate and chemical instability, which is why its formulations have relied on lyophilisation [6]; it is a textbook case of the problems described under peptide solubility. Selective changes to the glucagon sequence produced a peptide active at both GCGR and the GLP-1 receptor, and in diet-induced obese mice the resulting co-agonists reduced body fat through lower food intake together with higher energy expenditure [7]. Retatrutide extends this to three receptors; in obese mice the GCGR component was linked to increased energy expenditure, alongside intake effects attributed to GIPR and GLP-1R [8].
Points of confusion
- Agonist and antagonist are both research strategies. Antagonism was studied for its effect on fasting glucose, agonism within co-agonists for energy expenditure [4, 7].
- Liver-centred, not liver-only. Phenotypes such as reduced adiposity [3] show effects beyond hepatic glucose output.
- Counter-screen accordingly. Any GLP-1R agonist derived from glucagon-like sequences should be tested at GCGR, because small sequence changes alter selectivity [7]. The concentration–response design guide covers how to estimate and compare EC50 values, including specificity controls.
References
- 1.Jelinek LJ, Lok S, Rosenberg GB, et al. Expression cloning and signaling properties of the rat glucagon receptor. Science. 1993. PubMed 8384375
- 2.Zhang H, Qiao A, Yang D, et al. Structure of the full-length glucagon class B G-protein-coupled receptor. Nature. 2017. PubMed 28514451
- 3.Gelling RW, Du XQ, Dichmann DS, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003. PubMed 12552113
- 4.Wewer Albrechtsen NJ, Pedersen J, Galsgaard KD, et al. The Liver-α-Cell Axis and Type 2 Diabetes. Endocr Rev. 2019. PubMed 30920583
- 5.Müller TD, Finan B, Clemmensen C, et al. The New Biology and Pharmacology of Glucagon. Physiol Rev. 2017. PubMed 28275047
- 6.Li X, Wang Y, Chen Z, et al. Engineering Glucagon via Molecular and Formulation Strategies: From Natural Hormone to Effective and Stable Therapeutics. Chembiochem. 2025. PubMed 40459429
- 7.Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009. PubMed 19597507
- 8.Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022. PubMed 35985340