Affinage

GCGR

Glucagon receptor · UniProt P47871

Length
477 aa
Mass
54.0 kDa
Annotated
2026-06-10
47 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCGR is a class B1 G protein-coupled receptor for glucagon that governs hepatic glucose and lipid metabolism, islet hormone secretion, and systemic energy balance [PMID:34572144, PMID:bio_10.1101_2025.06.18.660434]. Cryo-EM structures of GCGR bound to heterotrimeric Gs reveal how glucagon and GLP-1R/GCGR dual agonists are recognized through the extracellular domain and the transmembrane-domain surface, with the first peptide residues dictating receptor selectivity and lipidated agonists engaging the TM1-TM2 cleft; Gs coupling alone can pre-open the intracellular cavity and rewire the orthosteric pocket (PMID:37549266, PMID:38346960), and NMR distance measurements confirm that glucagon selectively docks onto the extracellular surface of the transmembrane domain even without the extracellular domain (PMID:37332600). Active GCGR couples to Gs to drive cAMP-PKA signaling, which in hepatocytes activates a CREB → PGC-1α axis inducing the gluconeogenic enzymes PCK1 and G6PC (PMID:37048171); the scaffold RACK1 binds GCGR, PKA subunits, and CREB to organize this cascade at both the plasma membrane and nucleus, and its loss causes fasting hypoglycemia rescuable by active PKAcα [PMID:bio_10.1101_2025.06.18.660434]. In β-cells, GCGR activation elevates cAMP via adenylyl cyclase 5 to potentiate glucose-stimulated insulin secretion at physiological glucose (PMID:34572144), in part by destabilizing microtubules to mobilize insulin granules [PMID:bio_10.1101_2024.10.21.619544]. Distinct from GLP-1R and GIPR, β-arrestin recruitment to GCGR is phosphorylation-independent [PMID:bio_10.1101_2025.03.10.642457], and the balance of G protein versus β-arrestin engagement tunes signaling duration and glucose-lowering action (PMID:33933675). At the systemic level, hepatic GCGR mediates dual-agonist-driven lipid clearance and weight loss [PMID:bio_10.1101_2024.09.09.611134] and engages a liver→hypothalamic GABAergic→adipose UCP1 thermogenic axis (PMID:41654017), while interrupting glucagon signaling elevates amino acids that drive islet cell proliferation through SLC7A2 and mTORC1 [PMID:bio_10.1101_2024.08.06.606926]. GCGR also forms glucose-regulated nanoscale clusters at the membrane, with high glucose inducing receptor-level glucagon resistance (PMID:36824278).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2021 Medium

    Establishing that glucagon binds and selectively engages the GCGR transmembrane-domain surface answered how the peptide is recognized at the receptor and enabled biophysical study of the isolated TMD.

    Evidence 19F-NMR and paramagnetic relaxation enhancement with chemical fluorine and nitroxide labeling in micelles, nanodiscs, and truncated TMD constructs

    PMID:33369025 PMID:37332600

    Open questions at the time
    • Functional consequences of TMD-only binding not measured
    • Does not resolve full active-state coupling geometry
  2. 2021 High

    Resolving the role of β-cell GCGR in insulin secretion showed that glucagon potentiates GSIS at physiological glucose through AC5-driven cAMP, defining a glucose-dependent paracrine input to insulin release.

    Evidence GCGR/GLP-1R antagonists, genetically encoded cAMP reporter, AC isoform inhibitors, and β-cell-specific GCGR knockout mice

    PMID:34572144

    Open questions at the time
    • Mechanism coupling cAMP to granule release not defined here
    • AC5 selectivity relies on pharmacological inhibitors
  3. 2021 Medium

    Demonstrating that biased agonism tuning G protein versus β-arrestin-2 recruitment alters signaling duration linked receptor trafficking to in vivo efficacy.

    Evidence Cell-based G protein and β-arrestin-2 recruitment, internalization assays, molecular dynamics, and in vivo glucose/weight studies in mice

    PMID:33933675

    Open questions at the time
    • Co-agonists act on both GCGR and GLP-1R, complicating receptor attribution
    • Single lab
  4. 2023 High

    Cryo-EM of GCGR-Gs complexes with dual agonists explained the structural basis of ligand selectivity and dual agonism, including lipid-moiety engagement of the TM1-TM2 cleft.

    Evidence Cryo-EM structures of GCGR-Gs with three dual agonists plus pharmacological comparison

    PMID:37549266

    Open questions at the time
    • Captures agonist-bound active state only
    • Dynamics of selectivity switching not resolved
  5. 2023 Medium

    Defining the hepatic GCGR→PKA→CREB→PGC-1α cascade placed gluconeogenic gene induction (PCK1, G6PC) downstream of receptor activation by epistasis.

    Evidence Pathway inhibitors, GCGR overexpression, and phospho-/protein readouts in primary flounder hepatocytes

    PMID:37048171

    Open questions at the time
    • Fish ortholog; mammalian conservation inferred
    • Single lab
  6. 2023 Medium

    Super-resolution imaging revealed glucose-regulated GCGR nanoclustering and identified receptor-level glucagon resistance under high glucose.

    Evidence dSTORM imaging and cAMP-PKA assays in HepG2 and hepatic cells

    PMID:36824278

    Open questions at the time
    • Mechanism linking cluster size to signaling efficiency unresolved
    • Single cell-line system
  7. 2024 High

    A ligand-free GCGR-Gs structure showed that Gs alone can open the intracellular cavity and reorganize the orthosteric pocket, capturing a transitional pre-active conformation.

    Evidence Cryo-EM of nucleotide-free GCGR-Gs without cognate ligand, with comparison across GLP-1R/GCGR/GIPR

    PMID:38346960

    Open questions at the time
    • Physiological frequency of ligand-free Gs coupling unknown
    • Functional output of this state not measured
  8. 2024 Medium

    Linking hepatic GCGR to lipid handling, dual-agonist-induced CD9 upregulation was shown to limit steatosis via CFD/FLI1 ubiquitination, connecting GCGR agonism to fatty acid metabolism.

    Evidence Hepatic CD9 loss-of-function, cotadutide treatment, ubiquitination and rescue assays

    PMID:38837628

    Open questions at the time
    • Direct receptor-to-CD9 signaling step not defined
    • Single lab
  9. 2024 Medium

    Identifying SLC7A2/mTORC1 as the pathway driving islet cell proliferation upon loss of glucagon signaling established an amino-acid nutrient-sensing axis downstream of GCGR loss.

    Evidence Six models of interrupted glucagon signaling across zebrafish, rodent, and human islets, with rapamycin and SLC7A2 deficiency (preprint)

    PMID:bio_10.1101_2024.08.06.606926

    Open questions at the time
    • Preprint, not peer-reviewed
    • Hyperaminoacidemia as the proximal trigger inferred
  10. 2024 Low

    Hepatic GCGR was shown to be required for dual-agonist superior lipid clearance and weight loss versus GLP-1R mono-agonism.

    Evidence Dual agonist vs semaglutide comparison in hepatic GCGR models, lipid measurements (preprint)

    PMID:bio_10.1101_2024.09.09.611134

    Open questions at the time
    • Preprint with limited molecular-level mechanism
    • Single lab
  11. 2024 Medium

    Dual GCGR/GLP1R activation was tied to epigenetic control of intestinal fibrosis via reduced H3K9 lactylation and EMT.

    Evidence Receptor knockdown and dual agonist treatment, lactylation and EMT markers, in vivo fibrosis models and patient tissue

    PMID:40041889

    Open questions at the time
    • GCGR-specific contribution not isolated from GLP1R
    • Single lab
  12. 2025 Medium

    RACK1 was identified as a dual-compartment scaffold organizing GCGR-PKA at the membrane and PKAcα-CREB in the nucleus, providing the structural logic for hepatic gluconeogenic signaling.

    Evidence Co-IP, GST pulldown, PLA, fractionation, hepatic RACK1 knockout mice, and rescue with constitutively active PKAcα (preprint)

    PMID:bio_10.1101_2025.06.18.660434

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct RACK1-GCGR interface not mapped structurally
  13. 2025 Medium

    ALKBH5, a PKA-phosphorylated m6A demethylase, was placed as an upstream requirement for full hepatic GCGR pathway activity, linking RNA modification to glucagon glucose control.

    Evidence Hepatocyte-specific Alkbh5 knockout, knockdown, PKA phosphorylation and fractionation assays

    PMID:40014709

    Open questions at the time
    • Molecular targets of ALKBH5 demethylation in this axis not specified
    • Single study
  14. 2025 Medium

    Phosphoproteomics established that β-arrestin recruitment to GCGR is phosphorylation-independent, distinguishing it from GLP-1R and GIPR.

    Evidence Mass spectrometry C-tail mapping, mutagenesis, β-arrestin recruitment and cAMP assays (preprint)

    PMID:bio_10.1101_2025.03.10.642457

    Open questions at the time
    • Preprint, single lab
    • Structural basis for phosphorylation-independent arrestin engagement unknown
  15. 2025 Medium

    GCGR was shown to regulate β-cell microtubule dynamics, destabilizing MTs to mobilize insulin granules and enhance GSIS, defining a mechanistic link between receptor activation and secretion.

    Evidence Chemical agonists/antagonists with live MT imaging and GSIS in mouse and human β-cells (preprint)

    PMID:bio_10.1101_2024.10.21.619544

    Open questions at the time
    • Preprint
    • Signaling intermediates linking cAMP/PKA to MT destabilization not defined
  16. 2025 Medium

    GCGR agonism was shown to drive a liver→hypothalamic GABAergic→adipose UCP1 thermogenic axis, and hepatic GCGR to be required for AMPK/mTOR nutrient-sensing responses to caloric restriction.

    Evidence Chronic agonist treatment with metabolic cage and UCP1 readouts; liver-specific and global GCGR knockout mice across diets (one preprint)

    PMID:41654017 PMID:bio_10.1101_2025.05.13.653849

    Open questions at the time
    • Inter-organ signal from liver to brain not molecularly identified
    • Caloric-restriction study is a preprint

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structurally defined Gs-coupled, phosphorylation-independent arrestin behavior of GCGR is integrated with its scaffold-dependent compartmentalized PKA/CREB signaling and inter-organ axes into a unified, druggable mechanism remains open.
  • No structure of GCGR-β-arrestin complex
  • RACK1-GCGR and liver-brain signals lack molecular interface definition
  • Several systemic-axis findings remain in preprint

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
CREB1GCGGNASPRKACAPRKAR2ARACK1
Complex memberships
GCGR-Gs complexRACK1-GCGR-PKA scaffold complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Cryo-EM structures of GCGR in complex with heterotrimeric Gs protein and three GLP-1R/GCGR dual agonists (peptide 15, MEDI0382/cotadutide, SAR425899) identified key residues responsible for ligand recognition and dual agonism. Distinct side-chain orientations within the first three residues of the peptide ligand determine receptor selectivity, and ECL1 conformation of GCGR differs from GLP-1R in response to dual agonists. The lipid moiety of MEDI0382 interacts with the TM1-TM2 cleft of GCGR, explaining its increased potency at GCGR. Cryo-electron microscopy structural determination with pharmacological data comparison Proceedings of the National Academy of Sciences of the United States of America High 37549266
2024 Cryo-EM structure of ligand-free GCGR in complex with Gs protein (without cognate ligand) revealed that Gs protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket. A segment of GCGR ECL2 partially occupies the peptide-binding site in this ligand-free state, representing a transitional conformation distinct from the active agonist-bound state. Cryo-electron microscopy structural determination Cell discovery High 38346960
2023 In primary hepatocytes of Japanese flounder, glucagon promotes gluconeogenesis via sequential GCGR → PKA → CREB → PGC-1α signaling, with downstream induction of gluconeogenic enzymes PCK1 and G6PC. GCGR inhibition reduced phosphorylated CREB and PGC-1α protein, while GCGR overexpression had the opposite effect. Pharmacological inhibitors of pathway components, gene overexpression, mRNA and protein expression analysis in primary hepatocytes Cells Medium 37048171
2021 Glucagon potentiates insulin secretion via β-cell GCGR at physiological (but not high) glucose concentrations. GCGR activation independently evokes cAMP elevation via adenylyl cyclase 5 (AC5) in β-cells; at high glucose, AC5-driven cAMP elevation bypasses GCGR. β-cell-specific GCGR knockout mice showed more severe glucose intolerance on high-fat diet, and GCGR activation promoted glucose-stimulated insulin secretion more than GLP-1R under nutrient overload. GCGR/GLP-1R antagonists on single β-cells, α-β cell clusters, and isolated islets; genetically encoded cAMP fluorescence indicator (RAB-ICUE); AC family inhibitors; β-cell-specific GCGR knockout mice Cells High 34572144
2021 Partial agonism and reduced β-arrestin-2 recruitment at GCGR and GLP-1R (by OXM-derived co-agonists) was associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo, demonstrating that the balance between G protein and β-arrestin-2 recruitment modulates GCGR/GLP-1R signaling duration. Cell-based assays for G protein and β-arrestin-2 recruitment; receptor internalization assays; molecular dynamics simulations; in vivo glucose homeostasis and weight loss studies in mice Molecular metabolism Medium 33933675
2023 Using dSTORM super-resolution imaging, GCGR was found to form nanoscale clusters on HepG2 cell membranes. High glucose promoted GCGR expression and formation of larger clusters. Under high glucose conditions, glucagon stimulation did not suppress GCGR levels as effectively as under low glucose and failed to increase downstream cAMP-PKA signaling, indicating high glucose induces glucagon resistance at the receptor level. Direct stochastic optical reconstruction microscopy (dSTORM); cAMP-PKA signaling assays; hepatoma cell and hepatic cell comparison iScience Medium 36824278
2021 19F-NMR studies of GCGR in detergent micelles and nanodiscs were enabled by post-translational chemical introduction of fluorine-19 probes on indigenous cysteines with sequence-specific assignment. Addition of the negative allosteric modulator NNC0640 to the transmembrane domain of GLP-1R (but relevant for GCGR comparison) was required for long-time stability in NMR experiments, revealing allosteric effects from NAM binding to the TMD. 19F-NMR spectroscopy in solution; nanodisc and detergent micelle reconstitution; post-translational fluorine labeling The FEBS journal Medium 33369025
2023 Paramagnetic NMR relaxation enhancement with dual fluorine-19/nitroxide spin-label labeling showed that glucagon ligand binds to GCGR by selective interaction with the extracellular surface of the transmembrane domain (TMD), and this selectivity is preserved even in the TMD construct lacking the extracellular domain (ECD). Cross-reactivity: GLP-1 also interacts with GCGR extracellular surface. Paramagnetic NMR relaxation enhancement; dual labeling (19F on receptor, nitroxide spin labels on peptide ligands); truncated TMD constructs iScience Medium 37332600
2025 Scaffolding protein RACK1 directly binds GCGR, PKA regulatory subunit RIIα, PKA catalytic subunit PKAcα, and CREB, functioning as a dual-compartment scaffold that assembles GCGR–PKA complexes at the plasma membrane and PKAcα–CREB complexes in the nucleus. Acute hepatic RACK1 deficiency impaired PKAcα translocation, CREB phosphorylation, and gluconeogenic gene expression, causing fasting hypoglycemia; these defects were rescued by constitutively active PKAcα expression. Co-immunoprecipitation, GST pulldown, proximity ligation assays, subcellular fractionation, confocal microscopy, hepatic RACK1 knockout mice, functional rescue with constitutively active PKAcα bioRxivpreprint Medium bio_10.1101_2025.06.18.660434
2024 GCGR agonism by the dual agonist cotadutide upregulated CD9 in the liver. CD9 deficiency exacerbated hepatic steatosis via complement factor D (CFD)-regulated fatty acid metabolism; specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes by regulating CFD expression through ubiquitination-proteasomal degradation of FLI1. Blockade of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Hepatic CD9 knockdown/knockout; cotadutide treatment; gene expression analysis; ubiquitination assay; functional rescue experiments Advanced science Medium 38837628
2025 ALKBH5, an RNA m6A demethylase, is phosphorylated by protein kinase A (PKA) and translocates to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces GCGR signaling; ALKBH5 was identified as acting upstream of and required for full GCGR pathway activity in the liver. This places ALKBH5 as a regulator of the GCGR signaling pathway in hepatic glucose homeostasis. Hepatocyte-specific Alkbh5 knockout mice; targeted knockdown; PKA phosphorylation assay; subcellular fractionation Science Medium 40014709
2024 Hepatic GCGR is required for the superior weight loss and lipid clearance effects of the dual GCGR/GLP1R agonist BI 456908. The dual agonist achieved superior weight loss compared to selective GLP1R agonist semaglutide specifically through hepatic GCGR engagement, and hepatic GCGR facilitated plasma and liver lipid clearance stimulated by the dual agonist. Dual agonist vs. GLP1R mono-agonist comparison in vivo; hepatic GCGR-specific models; plasma and liver lipid measurement bioRxivpreprint Low bio_10.1101_2024.09.09.611134
2025 GCGR agonism recruits GABAergic signaling in the medial basal hypothalamus to promote UCP1-dependent thermogenesis in adipose tissue and drive weight loss in obese mice, establishing a liver→brain→fat axis activated by GCGR agonism. Chronic GCGR agonist treatment in obese mice; metabolic cage studies; GABAergic signaling pathway dissection; UCP1 protein measurement in adipose tissue; thermoneutral housing controls 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 C-tail phosphorylation is a critical determinant driving GPCR-β-arrestin complex formation and regulating cAMP production. Proteomic identification of C-tail phosphorylation sites by mass spectrometry; mutagenesis of phosphorylated residues; β-arrestin recruitment assays; cAMP production assays bioRxivpreprint Medium bio_10.1101_2025.03.10.642457
2024 Dual activation of GCGR and GLP1R reduced H3K9 lactylation in intestinal epithelial cells (resulting from reduced lactate accumulation) and ameliorated intestinal fibrosis through reduced epithelial-to-mesenchymal transition (EMT). Downregulation of GCGR and GLP1R in fibrotic tissue led to lactate accumulation and H3K9 lactylation-driven EMT. GCGR/GLP1R knockdown and dual agonist treatment; H3K9 lactylation measurement; EMT marker analysis; in vivo fibrosis models; patient tissue analysis Acta pharmaceutica Sinica. B Medium 40041889
2025 Liver-specific deletion of the glucagon receptor (Gcgr hep-/-) decreases hepatic AMP kinase activation in aging mice regardless of diet, and abolishes the caloric restriction-induced decrease in hepatic mTOR activity seen in wild-type mice, demonstrating that hepatic GCGR is required for AMPK and mTOR nutrient sensing pathway responses to caloric restriction. Liver-specific GCGR knockout mice; global GCGR knockout mice; dietary intervention (caloric restriction, high-fat diet); AMPK and mTOR activity assays bioRxivpreprint Medium bio_10.1101_2025.05.13.653849
2024 Interruption of glucagon signaling (via GCGR antagonism/knockout across zebrafish, rodent, and human islet models) stimulates delta cell and beta cell proliferation via SLC7A2 (cationic amino acid transporter) and mTORC1-dependent mechanisms, establishing an amino acid-nutrient sensing pathway downstream of loss of GCGR action. Six models of interrupted glucagon signaling (zebrafish gcgr deficiency, rodent GCGR antagonism, transplanted human islets); rapamycin (mTORC1 inhibition); SLC7A2 global deficiency; proliferation and mass measurements bioRxivpreprint Medium bio_10.1101_2024.08.06.606926
2025 In β-cells, activating GCGR (GcgR) with chemical agonists induces microtubule (MT) destabilization in the absence of high glucose, while inhibiting GCGR with antagonists attenuates high glucose-induced MT destabilization. This MT destabilization facilitates movement of insulin secretory granules toward the plasma membrane to enhance GSIS, establishing GCGR as a regulator of β-cell MT dynamics and insulin secretion through a paracrine mechanism from α-cells. Chemical GCGR agonists and antagonists; live MT imaging in mouse and human β-cells; islet α/β cell ratio analysis; GSIS measurements bioRxivpreprint Medium bio_10.1101_2024.10.21.619544
2021 GLP-1R/GCGR knockdown in hepatic fibrosis models demonstrated that GCGR plays an important role in ameliorating CCl4-induced hepatic fibrosis. The dual agonist TB001 attenuated hepatic stellate cell activation via suppression of TGF-β/Smad signaling and blocked NFκB/IKBα inflammatory pathways and JNK-dependent hepatocyte apoptosis. GLP-1R and/or GCGR knockdown in liver fibrosis models; CCl4, ANIT, BDL, and Schistosoma japonicum rodent models; TGF-β/Smad, NFκB/IKBα, JNK pathway analysis Acta pharmaceutica Sinica. B Low 35646543
2025 Chlorogenic acid (CGA) and ferulic acid (FA) inhibit cardiac lipotoxic apoptosis by inhibiting GCGR/PPARα and GCGR/AMPK signaling pathways. GCGR inhibitor (Adomeglivant) reduced PA-induced apoptosis, confirming that palmitic acid induces cardiomyocyte lipotoxic apoptosis by activating GCGR. Molecular docking identified ASP1018 and THR1024 of GCGR as principal interaction sites for CGA and FA. GCGR inhibitor treatment; Ad-GCGR infection (overexpression); molecular docking; RT-PCR and western blot for GCGR/PPARα and GCGR/AMPK pathway markers; flow cytometry and mitochondrial function assays Phytomedicine Low 40466507

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular metabolism 107 36356832
2011 Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes. BMC genomics 73 21631939
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
2025 Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling. Science (New York, N.Y.) 41 40014709
2021 Glucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose. Cells 36 34572144
2021 Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis. Acta pharmaceutica Sinica. B 32 35646543
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 31 37549266
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
2024 Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency. Nature chemistry 25 38755312
2024 GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis. World journal of gastroenterology 23 39735270
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 Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins. Cell discovery 21 38346960
2024 Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells. Acta pharmaceutica Sinica. B 18 40041889
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
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 13 38065435
2021 Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist. Molecular metabolism 13 33933675
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 12 37800952
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
2025 Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. EBioMedicine 11 40479843
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
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 10 40399267
2023 Glucagon Promotes Gluconeogenesis through the GCGR/PKA/CREB/PGC-1α Pathway in Hepatocytes of the Japanese Flounder Paralichthys olivaceus. Cells 10 37048171
2024 The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection. Diabetes, obesity & metabolism 9 38560764
2021 Ligand-Receptor Interactions and Machine Learning in GCGR and GLP-1R Drug Discovery. International journal of molecular sciences 8 33920024
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
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 6 40958513
2024 CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 38837628
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 5 40466507
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 Tanshinone IIA improved psychological stress-induced embryo implantation disorders by inhibiting GC/GR signaling and promoting angiogenesis. Phytomedicine : international journal of phytotherapy and phytopharmacology 4 40499218
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
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 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 2 41246119
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
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

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