Affinage

GCGR

Glucagon receptor · UniProt P47871

Round 2 corrected
Length
477 aa
Mass
54.0 kDa
Annotated
2026-04-28
77 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCGR is a class B G protein-coupled receptor that serves as the principal mediator of glucagon's metabolic actions, coupling ligand binding to Gs-dependent cAMP elevation to drive hepatic gluconeogenesis, glycogenolysis, amino acid catabolism, and fatty acid oxidation (PMID:7507321, PMID:21631939, PMID:23185367). Glucagon engages GCGR through a two-site mechanism in which the peptide C-terminus binds the extracellular domain (ECD) and the N-terminus inserts into the transmembrane domain (TMD) pocket, with the ECD playing an obligate active role in receptor activation beyond simple affinity capture; stalk and ECL1 conformational rearrangements trigger TMD opening for G protein engagement (PMID:12724331, PMID:27226600, PMID:29300013). GCGR couples primarily to Gs and secondarily to Gi1 through a larger Gs interaction interface, recruits β-arrestin in a phosphorylation-independent manner distinct from related incretin receptors, and is inhibited by allosteric small-molecule antagonists that bind an extra-helical TM6–TM7 site to prevent TM6 outward movement [PMID:32193322, PMID:27111510, PMID:bio_10.1101_2025.03.10.642457]. Loss-of-function GCGR mutations cause glucagon cell adenomatosis characterized by multifocal α-cell hyperplasia and neoplasia due to interrupted glucagon feedback (PMID:25695890).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Molecular cloning of human GCGR from liver cDNA established it as a seven-transmembrane receptor that binds glucagon with high affinity and signals via cAMP, placing glucagon signaling within the GPCR superfamily and mapping the gene to chromosome 17q25.

    Evidence Heterologous expression in COS-7 cells with radioligand binding and cAMP assays; genomic Southern blot and in situ hybridization

    PMID:7507321 PMID:8144028

    Open questions at the time
    • No structural information on receptor architecture
    • Downstream effectors beyond cAMP not identified
    • Tissue-specific signaling differences not addressed
  2. 1995 High

    Identification of the Gly40Ser missense variant linked to NIDDM demonstrated that single amino acid changes in GCGR can reduce glucagon-binding affinity ~3-fold, establishing the receptor as a diabetes-relevant locus.

    Evidence Site-directed mutagenesis with radioligand binding in transfected cells combined with genetic association

    PMID:7773293

    Open questions at the time
    • Downstream signaling consequences of reduced affinity not measured
    • Causal role vs. association not definitively resolved
    • No structural basis for affinity loss
  3. 2003 High

    Systematic mutagenesis and chimeric receptor studies defined the two-site binding model: the ECD captures the glucagon C-terminus while three distinct TMD epitopes recognize the glucagon N-terminus, providing the first molecular framework for ligand selectivity.

    Evidence Site-directed mutagenesis, chimeric receptors, radioligand binding and cAMP assays

    PMID:12724331

    Open questions at the time
    • No atomic-resolution structure to confirm predicted contacts
    • Dynamics of binding transition not captured
    • Mechanism of signaling transduction from binding to G protein engagement undefined
  4. 2011 High

    Global Gcgr knockout mice revealed the full metabolic scope of GCGR signaling: loss abolished hepatic gluconeogenesis and amino acid catabolism while upregulating glycolysis and lipogenesis, establishing GCGR as a master regulator of hepatic fuel selection.

    Evidence Gcgr-/- mouse with tri-omic profiling (transcriptomics, proteomics, metabolomics)

    PMID:21631939

    Open questions at the time
    • Cell-autonomous vs. systemic effects not dissected
    • Compensatory hormonal changes (hyperglucagonemia, elevated GLP-1) confound interpretation
    • Tissue-specific contributions not resolved
  5. 2013 High

    The first crystal structure of the GCGR TMD at 3.4 Å revealed a uniquely extended TM1 stalk that positions the ECD for glucagon capture, providing atomic-level understanding of the two-site binding mechanism and identifying the large orthosteric pocket.

    Evidence X-ray crystallography (3.4 Å) with extensive mutagenesis and hybrid modeling

    PMID:23863937

    Open questions at the time
    • Structure captured only the TMD, not full-length receptor
    • No agonist-bound conformation
    • G protein coupling interface not visualized
  6. 2015 Medium

    Loss-of-function GCGR germline mutations were shown to cause glucagon cell adenomatosis, directly linking interrupted glucagon feedback through GCGR to α-cell hyperplasia and neoplasia in humans.

    Evidence Sequencing of GCGR exons in GCA patients with clinicopathological correlation and control genotyping

    PMID:25695890

    Open questions at the time
    • Precise mechanism by which absent signaling drives proliferation not defined
    • Small patient cohort
    • No functional reconstitution of identified mutations
  7. 2016 High

    The crystal structure of GCGR bound to MK-0893 revealed an unprecedented extra-helical allosteric antagonist site between TM6 and TM7 that blocks the TM6 outward movement required for G protein coupling, opening a new pharmacological modality for GCGR inhibition.

    Evidence X-ray crystallography (2.5 Å) of GCGR–MK-0893 complex with mutagenesis and cAMP assays

    PMID:27111510

    Open questions at the time
    • Whether other class B GPCRs share this site not established
    • Effect on β-arrestin recruitment not tested
    • In vivo relevance of allosteric inhibition mechanism not confirmed structurally
  8. 2016 High

    Covalent tethering experiments demonstrated that the GCGR ECD is an obligate active participant in signal transduction rather than a passive affinity trap, distinguishing GCGR from other class B GPCRs where the ECD requirement can be bypassed.

    Evidence Covalent peptide–TMD linkage with chimeric receptors and cAMP assays

    PMID:27226600

    Open questions at the time
    • Structural basis for ECD's active signaling role not determined
    • Which ECD residues mediate signaling vs. binding not dissected
  9. 2017 High

    The full-length inactive GCGR structure revealed the stalk adopts a β-strand (not α-helical) conformation forming a β-sheet with ECL1, resolving the structural basis for ECD–TMD communication and identifying the stalk/ECL1 as a conformational switch controlling ligand access.

    Evidence X-ray crystallography (3.0 Å full-length), HDX, disulfide crosslinking, molecular dynamics

    PMID:28514451

    Open questions at the time
    • Active-state full-length structure not yet available at this point
    • Mechanism by which stalk rearrangement transmits signal to TMD not fully defined
  10. 2018 High

    The crystal structure of GCGR bound to glucagon analogue NNC1702 captured the peptide-engaged state, showing that stalk and ECL1 undergo major secondary-structure rearrangements during activation and establishing a 'dual-binding-site trigger model' for class B GPCR activation.

    Evidence X-ray crystallography (3.0 Å, full-length GCGR–peptide complex)

    PMID:29300013

    Open questions at the time
    • G protein coupling geometry not captured in same structure
    • Dynamics of transition from inactive to active not resolved
  11. 2020 High

    Cryo-EM structures of GCGR–glucagon complexes with both Gs and Gi1 revealed the structural basis for G protein selectivity: Gs forms a larger interface with GCGR intracellular loops, explaining preferential Gs coupling while showing Gi1 engagement uses the same open cavity.

    Evidence Cryo-EM of two GCGR–G protein complexes with mutagenesis validation

    PMID:32193322

    Open questions at the time
    • Kinetic basis for Gs preference over Gi not addressed
    • βγ subunit contributions to selectivity not dissected
    • Gq coupling not tested
  12. 2021 High

    β-cell GCGR was shown to potentiate glucose-stimulated insulin secretion at physiological glucose via AC5-dependent cAMP elevation, with β-cell-specific GCGR knockout mice developing exacerbated glucose intolerance on high-fat diet, establishing a direct paracrine α→β cell glucagon circuit.

    Evidence Single β-cell and islet cAMP imaging, AC family inhibitors, β-cell-specific GCGR knockout mice

    PMID:34572144

    Open questions at the time
    • Relative contribution of GCGR vs. GLP-1R in β-cell cAMP generation under physiological conditions not quantified
    • Whether AC5 specificity is universal across species not confirmed
  13. 2023 High

    Multiple cryo-EM structures of GCGR with dual GLP-1R/GCGR agonists defined how the first three peptide residues determine receptor selectivity and how lipid moieties on agonists engage the TM1–TM2 cleft, providing a structural template for rational design of dual agonist therapeutics.

    Evidence Cryo-EM of three dual agonist–GCGR–Gs complexes with pharmacological validation

    PMID:37549266

    Open questions at the time
    • β-arrestin-biased signaling by dual agonists not structurally characterized
    • In vivo tissue-specific signaling outcomes of differential receptor engagement not resolved
  14. 2024 High

    Ligand-free cryo-EM structures showed that Gs protein alone can open the GCGR intracellular cavity and partially remodel the extracellular peptide-binding site, with ECL2 occupying the orthosteric pocket in the absence of peptide — demonstrating that G protein pre-coupling creates a transitional state facilitating agonist entry.

    Evidence Cryo-EM of ligand-free GCGR–Gs complex with structural comparison to ligand-bound states

    PMID:38346960

    Open questions at the time
    • Physiological relevance of ligand-free G protein pre-coupling not established in cells
    • Whether this mechanism operates for Gi coupling not tested
  15. 2024 Medium

    GCGR blockade was shown to drive δ-cell and β-cell proliferation through SLC7A2-dependent amino acid transport and mTORC1 activation, linking GCGR-regulated amino acid homeostasis to islet cell mass expansion across zebrafish, mouse, and human islet models.

    Evidence Multi-species models (zebrafish, rodent KO/antagonism, transplanted human islets), rapamycin inhibition, SLC7A2 knockout (preprint)

    PMID:bio_10.1101_2024.08.06.606926

    Open questions at the time
    • Not peer-reviewed
    • Mechanism by which elevated amino acids activate mTORC1 specifically in δ/β cells not defined
    • Long-term consequences of proliferation not assessed
  16. 2025 Medium

    RACK1 was identified as a dual-compartment scaffold that physically links GCGR to PKA subunits at the plasma membrane and PKAcα to CREB in the nucleus, with hepatic RACK1 deletion causing fasting hypoglycemia reversible by constitutively active PKAcα — establishing the first scaffolding mechanism for spatial organization of the glucagon–PKA–CREB cascade.

    Evidence Hepatic RACK1 deletion, co-IP, GST pulldown, proximity ligation assay, cell fractionation, PKAcα rescue (preprint)

    PMID:bio_10.1101_2025.06.18.660434

    Open questions at the time
    • Not peer-reviewed
    • Whether RACK1 scaffolding is GCGR-specific or shared with other Gs-coupled receptors not tested
    • Structural basis for RACK1–GCGR interaction not resolved
  17. 2025 Medium

    GCGR agonism was shown to engage hypothalamic GABAergic circuits that drive UCP1-dependent adipose thermogenesis, establishing a liver→brain→fat axis as the primary mechanism for GCGR-mediated energy expenditure and weight loss rather than appetite suppression.

    Evidence Chronic GCGR agonism in obese mice with metabolic cages, hypothalamic GABAergic manipulation, UCP1 quantification

    PMID:41654017

    Open questions at the time
    • Afferent signal from liver to hypothalamus not identified
    • Whether this axis operates in humans not established
    • Relative contribution of direct hepatic vs. CNS-mediated effects not quantified
  18. 2025 Medium

    β-arrestin recruitment to GCGR was shown to be phosphorylation-independent, contrasting sharply with GLP-1R and GIPR where C-tail phosphorylation is required — revealing receptor-specific desensitization mechanisms among closely related class B GPCRs.

    Evidence Mass spectrometry phosphosite identification, site-directed mutagenesis, β-arrestin recruitment and cAMP assays (preprint)

    PMID:bio_10.1101_2025.03.10.642457

    Open questions at the time
    • Not peer-reviewed
    • Structural basis for phosphorylation-independent β-arrestin engagement not determined
    • In vivo consequences for receptor desensitization and trafficking not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the identity of the afferent signal linking hepatic GCGR activation to hypothalamic thermogenic circuits, the structural basis for phosphorylation-independent β-arrestin recruitment, whether G protein pre-coupling operates physiologically in native hepatocytes, and the long-term safety implications of GCGR-driven islet cell proliferation for dual-agonist therapeutics.
  • Liver-to-brain signal mediating thermogenesis unidentified
  • No structure of GCGR–β-arrestin complex
  • Physiological relevance of ligand-free G protein pre-coupling untested in primary cells

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 2
Partners
AC5ARRB2CD9GNA5GNAI1RACK1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 The human glucagon receptor (GCGR) was cloned from a liver cDNA library; it encodes a 477-amino-acid seven-transmembrane G protein-coupled receptor that, when transfected into COS-7 cells, confers high-affinity [125I]glucagon binding and transduces signals leading to increases in intracellular cAMP. Rank-order potency of binding: glucagon > oxyntomodulin > GLP-1(7-36) amide >> GLP-2 = GIP = secretin. cDNA cloning, heterologous expression in COS-7 cells, radioligand binding assay, cAMP measurement Biochemical and Biophysical Research Communications High 7507321
1994 The GCGR gene maps to human chromosome 17q25, spans >5.5 kb with 12 introns, and encodes a receptor with 80% identity to rat GCGR. The cDNA-expressed receptor binds glucagon and signals via intracellular cAMP elevation. cDNA cloning from liver library, Southern blot, in situ hybridization to metaphase chromosomes, cAMP assay Gene High 8144028
1995 A missense mutation Gly40Ser in GCGR is associated with NIDDM; receptor binding studies in cultured cells expressing this mutant show approximately three-fold lower glucagon-binding affinity compared to wild-type, establishing a functional consequence of this variant. Site-directed mutagenesis, radioligand binding assay in transfected cells, genetic association study Nature Genetics High 7773293
2003 Three distinct epitopes on the extracellular face of the GCGR transmembrane core domain (at extracellular ends of TM2 and TM7, and the second extracellular loop/proximal TM4-TM5) determine specificity for the N-terminus of glucagon (residues Ser2, Gln3, Tyr10, Lys12). The N-terminal extracellular domain (ECD) determines specificity for the glucagon C-terminus, establishing a two-site binding model. Site-directed mutagenesis of receptor core domain, chimeric receptor construction, radioligand binding, cAMP functional assay The Journal of Biological Chemistry High 12724331
2003 Glucagon acting through GCGR promotes hepatic glucose output by stimulating glycogenolysis and gluconeogenesis, and inhibiting glycogenesis and glycolysis. In diabetic states, hyperglucagonemia and altered insulin-to-glucagon ratios contribute to hyperglycemia through excessive hepatic glucose production via GCGR. In vivo animal models and human physiological studies (review synthesizing mechanistic data) American Journal of Physiology. Endocrinology and Metabolism Medium 12626323
2013 Crystal structure of the seven-transmembrane helical domain of human GCGR resolved at 3.4 Å. The structure reveals a large ligand-binding pocket and a unique 'stalk' region extending three alpha-helical turns above the membrane plane on TM1, which positions the extracellular domain (~12 kDa) to form the glucagon-binding site. The ECD facilitates capture of glucagon peptide, enabling insertion of the glucagon N-terminus into the 7TM domain. Extensive site-specific mutagenesis and a hybrid glucagon-bound GCGR model provided molecular details of ligand recognition. X-ray crystallography (3.4 Å), site-directed mutagenesis, hybrid structural modeling Nature High 23863937
2013 Oxyntomodulin activates both GCGR and GLP-1R; simultaneous activation of both receptors reduces food intake and increases energy expenditure, with GLP-1R agonism counteracting the hyperglycemic effect of GCGR activation. This dual mechanism results in superior body weight lowering compared to selective GLP-1R agonism. In vivo pharmacological studies; human infusion studies; cell-based cAMP assays Molecular Metabolism Medium 24749050
2015 Full-length GCGR can adopt open and closed conformations involving extensive contacts between the ECD and 7TM domain. Molecular dynamics and disulfide crosslinking studies indicate that apo-GCGR exists in both conformations, and peptide ligand binding (plus a monoclonal antibody) stabilizes an open/elongated conformation consistent with a conformational selection mechanism for glucagon binding. HDX studies identified the stalk and first extracellular loop as key modulators of peptide binding. Molecular dynamics simulations, disulfide crosslinking, electron microscopy, hydrogen/deuterium exchange (HDX), crystal structure of TMD Nature Communications High 26227798
2015 Loss-of-function GCGR germline mutations (including homozygous stop mutations and compound heterozygous missense mutations) cause glucagon cell adenomatosis (GCA) — multifocal hyperplastic/neoplastic disease of pancreatic glucagon cells. By interrupting GCGR signaling, mutations drive glucagon cell hyperplasia and neoplasia, with mutation carriers exhibiting greater numbers and larger tumors than wild-type patients. Sanger and next-generation sequencing of all GCGR exons, clinicopathological correlation, genotyping in 2560 controls The Journal of Clinical Endocrinology and Metabolism Medium 25695890
2016 The small-molecule GCGR antagonist MK-0893 binds to an allosteric extra-helical site located between TM6 and TM7 extending into the lipid bilayer, outside the canonical 7TM bundle. This binding prevents the outward movement of TM6 required for G-protein coupling, thereby blocking receptor activation. Key residues at this novel site were confirmed by mutagenesis. X-ray crystallography (2.5 Å resolution of GCGR-MK-0893 complex), site-directed mutagenesis, functional cAMP assay Nature High 27111510
2016 The ECD of GCGR is strictly required for receptor activation even when the peptide hormone is covalently linked to the TMD, unlike some other class B GPCRs (e.g., CRF1R, PTH1R, PAC1R) where ECD requirement can be bypassed. This demonstrates that the GCGR ECD plays a direct, active role in signaling beyond merely serving as an affinity trap. Chimeric receptor construction, covalent peptide-TMD linkage experiments, cAMP functional assays The Journal of Biological Chemistry High 27226600
2017 Crystal structure of full-length GCGR at 3.0 Å in inactive conformation reveals the stalk connecting the ECD and TMD adopts a β-strand conformation (not α-helix). The first extracellular loop (ECL1) forms a β-hairpin that interacts with the stalk to create a compact β-sheet structure. HDX, disulfide crosslinking and MD studies demonstrate that the stalk and ECL1 have critical roles in modulating peptide ligand binding and receptor activation. X-ray crystallography (3.0 Å, full-length), hydrogen-deuterium exchange, disulfide crosslinking, molecular dynamics Nature High 28514451
2018 Crystal structure of full-length GCGR in complex with glucagon analogue NNC1702 at 3.0 Å reveals the molecular details of peptide-receptor interactions. The stalk and ECL1 undergo major conformational changes (secondary structure rearrangements) during peptide binding, forming key contacts with the peptide. The ECD-TMD relative orientation changes markedly relative to the inactive structure. A 'dual-binding-site trigger model' is proposed for GCGR activation requiring conformational changes in the stalk, ECL1, and TMD. X-ray crystallography (3.0 Å, full-length GCGR-peptide complex), structural comparison Nature High 29300013
2011 Complete ablation of hepatic glucagon receptor function in Gcgr-/- mice causes major metabolic alterations: significant down-regulation of gluconeogenesis, amino acid catabolism, and fatty acid oxidation, with up-regulation of glycolysis, fatty acid synthesis, and cholesterol biosynthesis. Plasma metabolite changes include decreased glucose and glucose-derived metabolites, and increased amino acids, cholesterol, and bile acids. Global Gcgr knockout mouse model, liver transcriptomics (Affymetrix arrays), liver proteomics (iTRAQ), plasma metabolite profiling (~200 analytes, mass spectrometry), pathway analysis BMC Genomics High 21631939
2012 GRA1, a small-molecule GCGR antagonist, blocks glucagon binding to human GCGR and antagonizes glucagon-induced cAMP accumulation with nanomolar potency. It inhibits glycogenolysis in primary human hepatocytes and perfused liver from humanized GCGR mice. In monkeys, GRA1 treatment down-regulates hepatic genes involved in amino acid catabolism and increases circulating amino acids, demonstrating GCGR's role in hepatic amino acid metabolism. In vitro cAMP assay, radioligand competition binding, primary human hepatocyte glycogenolysis assay, perfused liver from hGCGR transgenic mice, in vivo glucose tolerance in rodents and primates, hepatic gene-expression profiling PLoS One High 23185367
2018 In Gcgr-/- mice, GLP-2 receptor (GLP-2R) signaling controls circulating bile acid levels and their relative species proportions but is not essential for body weight control or glucose homeostasis. Gpbar1 (TGR5) does not mediate elevated proglucagon-derived peptide levels or major metabolic phenotypes in Gcgr-/- mice despite elevated bile acids. Small bowel growth in Gcgr-/- mice requires intact GLP-2R signaling. Double-knockout mouse models (Gcgr-/-:Gpbar1-/-, Gcgr-/-:Glp2r-/-), glucose tolerance testing, insulin measurement, bile acid profiling, intestinal mass measurement Molecular Metabolism High 29937214
2020 Computational free-energy landscape analysis reveals that GCGR activation follows a combined mechanism: the agonist (glucagon) first stabilizes the receptor in a 'pre-activated' state, which is then fully activated upon G protein binding — contrasting with the classical model of agonist-driven TM6 opening. This mechanism is consistent with cryo-EM structural data. Free-energy landscape computation (molecular dynamics simulations), comparison with cryo-EM structural data Proceedings of the National Academy of Sciences of the United States of America Medium 32571939
2020 Cryo-EM structures of GCGR bound to glucagon in complex with either Gs or Gi1 heterotrimeric G proteins reveal that both Gs and Gi1 bind in a similar open intracellular cavity. GCGR's Gs-binding selectivity is explained by a larger interaction interface with Gs; specific intracellular loop conformational differences are key selectivity determinants. Mutagenesis of identified residues confirmed their roles in transducer engagement. Cryo-electron microscopy structural determination, site-directed mutagenesis, functional G protein coupling assays Science High 32193322
2021 Glucagon potentiates glucose-stimulated insulin secretion (GSIS) via β-cell GCGR at physiological but not high glucose concentrations. GCGR activation elevates cAMP via adenylyl cyclase 5 (AC5) in β-cells, independently of high-glucose-induced cAMP elevation via the same AC5. High glucose concentration bypasses the GCGR requirement for cAMP elevation and insulin secretion. β-cell-specific GCGR knockout mice develop more severe glucose intolerance on high-fat diet. GCGR/GLP-1R antagonists in single β-cells, α-β cell clusters, and isolated islets; RAB-ICUE cAMP fluorescence indicator; specific AC family inhibitors; β-cell-specific GCGR knockout mice; high-fat diet metabolic phenotyping Cells High 34572144
2021 Ligand-specific reduction of β-arrestin-2 recruitment at GCGR (via partial agonism of OXM-derived co-agonists) slows GLP-1R internalization and prolongs glucose-lowering action in vivo, while retaining GCGR-mediated weight loss via increased energy expenditure. This establishes that GCGR co-agonism contributes weight loss through energy expenditure mechanisms distinct from food intake suppression. Cell-based β-arrestin-2 recruitment assays, receptor internalization assays, molecular dynamics simulations, in vivo glucose homeostasis and weight loss studies in mice Molecular Metabolism Medium 33933675
2021 19F-NMR studies of detergent-reconstituted GCGR in micelles and nanodiscs reveal that the negative allosteric modulator NNC0640 binding to the GCGR transmembrane domain confers the long-time stability required for NMR experiments, and produces distinct allosteric effects on receptor dynamics detectable via 19F probes on indigenous cysteines. 19F-NMR spectroscopy, paramagnetic relaxation enhancement, detergent/nanodisc reconstitution, post-translational chemical labeling The FEBS Journal Medium 33369025
2023 Cryo-EM structures of GLP-1R and GCGR each in complex with Gs protein and three different dual GLP-1R/GCGR agonists (peptide 15, cotadutide/MEDI0382, SAR425899) reveal that distinct side chain orientations within the first three peptide residues determine receptor selectivity. The middle region of dual agonists engages ECL1, ECL2, and top of TM1, causing specific conformational changes; dual agonists reshape ECL1 conformation of GLP-1R relative to GCGR. Lipid moiety of MEDI0382 interacts with TM1-TM2 cleft of GCGR, explaining its increased potency at GCGR. Cryo-electron microscopy (high-resolution), structural analysis of multiple agonist-receptor-Gs complexes, pharmacological validation Proceedings of the National Academy of Sciences of the United States of America High 37549266
2023 Super-resolution dSTORM imaging of HepG2 cells reveals that GCGR forms nanoscale clusters on the plasma membrane. High glucose promotes increased GCGR expression and formation of larger, more numerous clusters. Under high glucose, glucagon stimulation fails to suppress GCGR cluster levels or increase downstream cAMP-PKA signaling, demonstrating that high glucose induces glucagon resistance at the receptor level. Hepatoma cells display stronger glucagon resistance than normal hepatic cells under high glucose. Direct stochastic optical reconstruction microscopy (dSTORM), cAMP-PKA signaling assays, GCGR expression quantification in HepG2 vs. primary hepatic cells iScience Medium 36824278
2023 GLP-1 selectively binds the extracellular surface of GLP-1R transmembrane domain (TMD) even in the absence of the ECD, as shown by paramagnetic NMR. Cross-reactivity of GLP-1R with glucagon and GCGR with GLP-1 was demonstrated, providing molecular evidence of receptor cross-reactivity in solution relevant to dual agonist pharmacology. Paramagnetic NMR relaxation enhancement, dual 19F/nitroxide spin labeling of receptor and peptide ligands, solution-state measurements of GLP-1R-TMD and GCGR iScience Medium 37332600
2023 In Japanese flounder hepatocytes, glucagon promotes gluconeogenesis through a defined GCGR/PKA/CREB/PGC-1α pathway: GCGR activation increases Gs/adenylyl cyclase activity, elevating cAMP, which activates PKA to phosphorylate CREB, which induces PGC-1α expression, leading to upregulation of gluconeogenic genes pck1 and g6pc and glucose production. Each step was validated by specific inhibitors and GCGR overexpression. Primary hepatocyte culture, pharmacological inhibitors of GCGR/PKA/CREB/PGC-1α, gcgr gene overexpression, mRNA/protein quantification, glucose production assay Cells Medium 37048171
2024 Cryo-EM structures of human GLP-1R, GCGR, and GIPR in complex with Gs proteins in the absence of cognate ligands reveal that Gs protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket. In ligand-free GCGR, a segment of ECL2 partially occupies the peptide-binding site. These ligand-free structures demonstrate that Gs protein can mobilize the intracellular transmembrane domain and rearrange the extracellular region to a transitional conformation facilitating peptide N-terminus entry. Cryo-electron microscopy (high-resolution), structural comparison of ligand-free vs. ligand-bound receptor-Gs complexes Cell Discovery High 38346960
2024 ALKBH5, an RNA m6A demethylase, is phosphorylated by protein kinase A (PKA), causing its translocation from the nucleus to the cytosol. Hepatocyte-specific Alkbh5 deletion inhibits GCGR signaling pathways and reduces glucose and lipid levels. ALKBH5 regulates glucose homeostasis through the GCGR pathway and lipid homeostasis through mTORC1, establishing ALKBH5 as a regulator upstream of GCGR-mediated metabolic signaling. Hepatocyte-specific conditional knockout, PKA phosphorylation assays, metabolic phenotyping (glucose/lipid measurements), pathway analysis Science Medium 40014709
2024 CD9 (tetraspanin) mediates hepatic effects of GCGR agonism. GCGR activation upregulates hepatic CD9 expression. CD9 deficiency exacerbates diet-induced hepatic steatosis via complement factor D (CFD)-regulated fatty acid metabolism; CD9 modulates hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via ubiquitination-proteasomal degradation of FLI1. Blockade of CD9 abolishes cotadutide (GCGR/GLP-1R agonist)-induced remission of hepatic steatosis. Hepatic CD9 knockdown/knockout, GCGR agonist treatment (cotadutide), ubiquitination assays, adipose thermogenesis measurement, hepatic gene expression Advanced Science Medium 38837628
2024 Downregulation of GCGR and GLP1R in stenotic ileum of Crohn's disease patients and fibrotic mouse colon leads to accumulation of metabolic lactate, resulting in histone H3K9 lactylation in epithelial cells and epithelial-to-mesenchymal transition (EMT)-driven intestinal fibrosis. Dual GCGR/GLP1R activation by peptide 1907B reduces H3K9 lactylation and ameliorates intestinal fibrosis in vivo, establishing GCGR's role in regulating epithelial energy metabolism and EMT. Patient tissue analysis, chronic colitis mouse model, histone lactylation assays, EMT marker analysis, dual agonist treatment in vivo Acta Pharmaceutica Sinica B Medium 40041889
2024 Hepatic GCGR is the critical mediator of superior weight loss and lipid clearance achieved by the dual GCGR/GLP1R agonist BI 456908 compared to selective GLP1R agonism. Hepatic GCGR engagement facilitates plasma and liver lipid clearance, demonstrating a direct hepatic GCGR contribution to the metabolic efficacy of dual agonism. Comparison of dual agonist (BI 456908) vs. selective GLP1R agonist (semaglutide) in vivo; liver-specific mechanistic assessment; body weight and lipid profiling bioRxiv (preprint)preprint Low bio_10.1101_2024.09.09.611134
2025 RACK1 (Receptor for Activated C Kinase 1) functions as a dual-compartment scaffold for the hepatic glucagon-PKA-CREB signaling axis. RACK1 directly binds GCGR, PKA regulatory (RIIα) and catalytic (PKAcα) subunits, and CREB, assembling GCGR-PKA complexes at the plasma membrane and PKAcα-CREB complexes in the nucleus. Loss of hepatic RACK1 impairs PKAcα translocation, CREB phosphorylation, and gluconeogenic gene expression, causing fasting hypoglycemia. These defects are rescued by constitutively active PKAcα. Acute hepatic RACK1 deletion (mouse liver), co-immunoprecipitation, GST pulldown, proximity ligation assay, confocal microscopy, cell fractionation, glucose/pyruvate tolerance tests, hepatocyte glucose production assay, PKAcα W196R rescue experiment bioRxiv (preprint)preprint Medium bio_10.1101_2025.06.18.660434
2025 GCGR agonism in obese mice recruits GABAergic signaling in the medial basal hypothalamus to promote UCP1-dependent thermogenesis in adipose tissue, increase caloric expenditure, and drive negative energy balance. This establishes a liver→brain→fat axis for GCGR-mediated weight loss, with weight loss occurring primarily through augmented metabolic rate rather than food intake reduction. Chronic GCGR agonist treatment in obese mice, metabolic cage studies at room temperature and thermoneutrality, hypothalamic circuit manipulation (GABAergic signaling), UCP1 protein measurement in adipose tissue, body composition analysis Molecular Metabolism Medium 41654017
2025 Ligand-induced β-arrestin recruitment to GCGR proceeds in a phosphorylation-independent manner, in contrast to GLP-1R and GIPR where phosphorylation of C-terminal tail residues is a critical determinant driving GPCR-β-arrestin complex formation. Mutagenesis of identified C-tail phosphorylation sites confirms unique receptor-specific effects on β-arrestin recruitment and cAMP production. Proteomic identification of C-tail phosphorylation sites (mass spectrometry), site-directed mutagenesis, β-arrestin recruitment assay, cAMP assay bioRxiv (preprint)preprint Medium bio_10.1101_2025.03.10.642457
2024 Interruption of glucagon signaling (via GCGR antagonism or Gcgr knockout) augments delta cell and beta cell proliferation in mouse, zebrafish, and transplanted human islets. This proliferative response requires the cationic amino acid transporter SLC7A2 and mTORC1 activation — established by rapamycin sensitivity and SLC7A2-deficient models — linking GCGR-mediated amino acid sensing to islet non-alpha cell growth. Multiple models (zebrafish gcgr deficiency, rodent GCGR antagonism/KO, transplanted human islets), rapamycin inhibition, SLC7A2 global knockout, delta/beta cell proliferation quantification bioRxiv (preprint)preprint Medium bio_10.1101_2024.08.06.606926
2025 Avian GCGR is expressed at high levels in adipocytes (unlike mammalian GCGR which is minimally expressed in adipose). Avian GCGR or constitutively active human GCGR variant (GCGRH339R) expressed in white adipose tissue of obese male mice effectively promotes fat mobilization and sustained body weight loss, with decreased food intake partially contributing to weight reduction. This identifies adipose GCGR as a mechanism for continuous fat utilization. Cross-species single-nucleus RNA-sequencing, viral expression of avian GCGR and human GCGRH339R in mouse white adipose tissue, body composition and weight tracking, food intake measurement Nature Communications Medium 41315395
2025 Globally eliminating GCGR signaling (Gcgr KO) decreases median lifespan by 35% in lean mice and 54% in obese mice. Glucagon receptor signaling is indispensable for the metabolic benefits of caloric restriction: while CR reduces liver fat, serum triglycerides and cholesterol in wild-type mice, these benefits are absent in Gcgr KO mice. Liver-specific Gcgr deletion decreases hepatic AMPK activation in aging mice regardless of diet, and abolishes CR-mediated suppression of mTOR activity. Global and liver-specific Gcgr knockout mice, dietary manipulation (caloric restriction), metabolic phenotyping (liver fat, lipids), AMPK and mTOR activity measurements bioRxiv (preprint)preprint Medium bio_10.1101_2025.05.13.653849

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Glucagon and regulation of glucose metabolism. American journal of physiology. Endocrinology and metabolism 635 12626323
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2013 Structure of the human glucagon class B G-protein-coupled receptor. Nature 302 23863937
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2013 Insights into the structure of class B GPCRs. Trends in pharmacological sciences 182 24359917
2016 Extra-helical binding site of a glucagon receptor antagonist. Nature 178 27111510
2017 Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 173 28514451
1995 A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. Nature genetics 166 7773293
2013 Action and therapeutic potential of oxyntomodulin. Molecular metabolism 137 24749050
2020 Structural basis of Gs and Gi recognition by the human glucagon receptor. Science (New York, N.Y.) 130 32193322
1994 The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization. Gene 114 8144028
2018 Structure of the glucagon receptor in complex with a glucagon analogue. Nature 108 29300013
2022 BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular metabolism 101 36356832
2015 Conformational states of the full-length glucagon receptor. Nature communications 97 26227798
2008 Reviews in molecular biology and biotechnology: transmembrane signaling by G protein-coupled receptors. Molecular biotechnology 92 18240029
2004 Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry. Proteomics 77 15188402
2019 The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis. Nature communications 74 31586073
2011 Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes. BMC genomics 72 21631939
2003 Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. The Journal of biological chemistry 68 12724331
1994 Cloning and expression of a human glucagon receptor. Biochemical and biophysical research communications 66 7507321
2014 Functional consequences of glucagon-like peptide-1 receptor cross-talk and trafficking. The Journal of biological chemistry 61 25451942
2016 Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors. The Journal of biological chemistry 60 27226600
1996 Glucagon receptor gene mutation in essential hypertension. Nature genetics 55 8563746
2020 A combined activation mechanism for the glucagon receptor. Proceedings of the National Academy of Sciences of the United States of America 54 32571939
2015 Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. The Journal of clinical endocrinology and metabolism 52 25695890
2012 Anti-diabetic efficacy and impact on amino acid metabolism of GRA1, a novel small-molecule glucagon receptor antagonist. PloS one 48 23185367
2019 Antisense Inhibition of Glucagon Receptor by IONIS-GCGRRx Improves Type 2 Diabetes Without Increase in Hepatic Glycogen Content in Patients With Type 2 Diabetes on Stable Metformin Therapy. Diabetes care 45 30765435
2022 Role of Glucagon and Its Receptor in the Pathogenesis of Diabetes. Frontiers in endocrinology 39 35784565
1997 Tissue-specific and glucose-dependent expression of receptor genes for glucagon and glucagon-like peptide-1 (GLP-1). Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 36 9105899
2025 Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling. Science (New York, N.Y.) 32 40014709
2021 Glucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose. Cells 32 34572144
2021 Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis. Acta pharmaceutica Sinica. B 32 35646543
2016 DNA immunization combined with scFv phage display identifies antagonistic GCGR specific antibodies and reveals new epitopes on the small extracellular loops. mAbs 29 27211075
2023 Structural analysis of the dual agonism at GLP-1R and GCGR. Proceedings of the National Academy of Sciences of the United States of America 28 37549266
2024 Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency. Nature chemistry 25 38755312
2021 Gestational cadmium exposure impairs placental angiogenesis via activating GC/GR signaling. Ecotoxicology and environmental safety 23 34411824
2018 GLP-2 receptor signaling controls circulating bile acid levels but not glucose homeostasis in Gcgr-/- mice and is dispensable for the metabolic benefits ensuing after vertical sleeve gastrectomy. Molecular metabolism 23 29937214
2024 GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis. World journal of gastroenterology 21 39735270
2024 Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins. Cell discovery 20 38346960
2018 The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine. Molecular genetics and metabolism reports 18 30294546
2024 Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells. Acta pharmaceutica Sinica. B 13 40041889
2021 Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist. Molecular metabolism 13 33933675
2023 Evaluation of long acting GLP1R/GCGR agonist in a DIO and biopsy-confirmed mouse model of NASH suggest a beneficial role of GLP-1/glucagon agonism in NASH patients. Molecular metabolism 12 38065435
2021 Design and preparation of the class B G protein-coupled receptors GLP-1R and GCGR for 19 F-NMR studies in solution. The FEBS journal 12 33369025
2017 Population pharmacokinetics and pharmacodynamics of IONIS-GCGRRx, an antisense oligonucleotide for type 2 diabetes mellitus: a red blood cell lifespan model. Journal of pharmacokinetics and pharmacodynamics 11 28132162
2023 Alpinia katsumadai Hayata Volatile Oil Is Effective in Treating 5-Fluorouracil-Induced Mucositis by Regulating Gut Microbiota and Modulating the GC/GR Pathway and the mPGES-1/PGE2/EP4 Pathways. Journal of agricultural and food chemistry 10 37800952
2024 The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection. Diabetes, obesity & metabolism 9 38560764
2025 GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice. Nature communications 8 40399267
2025 Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. EBioMedicine 8 40479843
2021 Ligand-Receptor Interactions and Machine Learning in GCGR and GLP-1R Drug Discovery. International journal of molecular sciences 8 33920024
2023 Glucagon Promotes Gluconeogenesis through the GCGR/PKA/CREB/PGC-1α Pathway in Hepatocytes of the Japanese Flounder Paralichthys olivaceus. Cells 7 37048171
2018 Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists. Molecular and cellular endocrinology 7 30312651
2024 CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 38837628
2020 Graph theory-based reaction pathway searches and DFT calculations for the mechanism studies of free radical-initiated peptide sequencing mass spectrometry (FRIPS MS): a model gas-phase reaction of GGR tri-peptide. Physical chemistry chemical physics : PCCP 5 32073000
2025 Chlorogenic acid and ferulic acid in SMYAD alleviate diabetic cardiomyopathy by inhibiting cardiac lipotoxicity via GCGR/PPARα and GCGR/AMPK pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 4 40466507
2023 High glucose-induced glucagon resistance and membrane distribution of GCGR revealed by super-resolution imaging. iScience 4 36824278
2020 The V369M Gcgr knock-in mice are a precision medicine model of mild Mahvash disease. The Biochemical journal 4 32785645
2025 Strategic Design of Triple GLP-1R/GCGR/GIPR Agonists with Varied Receptor Potency: Achieving Comparable Glycemic and Weight Reduction Effects. Journal of medicinal chemistry 3 40958513
2023 Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR. iScience 3 37332600
2025 Tanshinone IIA improved psychological stress-induced embryo implantation disorders by inhibiting GC/GR signaling and promoting angiogenesis. Phytomedicine : international journal of phytotherapy and phytopharmacology 2 40499218
2025 DeepGCGR: an interpretable two-layer deep learning model for the discovery of GCGR-activating compounds. Chinese journal of natural medicines 2 41260780
2021 Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis. Bioscience reports 2 34002801
2025 Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide. Molecular metabolism 1 40619099
2025 Dual GIP/GLP1-RA, GCGR/GLP-1 RA and GLP1-RA for the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease with Type 2 Diabetes: A Systematic Review and Meta-analysis. TouchREVIEWS in endocrinology 1 41246119
2024 The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures. International journal of molecular sciences 1 39125959
2023 Evolution of GCGR family ligand-receptor extensive cross-interaction systems suggests a therapeutic direction for hyperglycemia in mammals. Acta biochimica et biophysica Sinica 1 37969012
2026 GCGR agonism requires GABAergic signaling in the medial basal hypothalamus to promote weight loss in obese mice. Molecular metabolism 0 41654017
2026 Design and biological evaluation of triagonist GLP-1R/GCGR/GIPR peptides as potential therapeutic agents for diabetes and obesity. RSC medicinal chemistry 0 41869515
2025 Novel Peptides as GIPR/GLP-1R/GCGR Triagonists for Treating Type 2 Diabetes Mellitus. ACS medicinal chemistry letters 0 40832525
2025 Case Report: Efficacy and safety of dose-escalated Mazdutide, a GLP-1/GCGR dual agonist, in an adolescent with obesity, type 2 diabetes, and hyperuricemia. Frontiers in endocrinology 0 41030857
2025 A novel GCGR/GLP-1R dual-agonist TB001 ameliorates kidney fibrosis via inhibiting PERK-mediated endoplasmic reticulum stress pathway. Frontiers in immunology 0 41280890
2025 Avian GCGR-mediated continuous fat utilization offers perspectives for obesity treatment. Nature communications 0 41315395
2022 Generation of an induced pluripotent stem cell (iPSC) line from a diabetic patient with glucagon receptor (GCGR) p.W83X mutation. Stem cell research 0 35381520