Details for: GCGR

Gene ID: 2642

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: GCGR

Ensembl ID: ENSG00000215644

Description: glucagon receptor

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • hepatocyte CL0000182
    CSI 5.59
    rCSI 10.01%
    PRS 99.34
  • renal alpha-intercalated cell CL0005011
    CSI 4.63
    rCSI 6.19%
    PRS 99.73
  • Mueller cell CL0000636
    CSI 3.39
    rCSI 7.73%
    PRS 99.24
  • periportal region hepatocyte CL0019026
    CSI 3.19
    rCSI 12.42%
    PRS 99.36
  • centrilobular region hepatocyte CL0019029
    CSI 2.92
    rCSI 7.62%
    PRS 99.26
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.75
    rCSI 4.44%
    PRS 99.35
  • kidney distal convoluted tubule epithelial cell CL1000849
    CSI 0.56
    rCSI 5.95%
    PRS 99.32

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary The [GCGR](/details-gene/2642) gene encodes the glucagon receptor, a class B G-protein coupled receptor (GPCR) that plays a central role in glucose metabolism and energy homeostasis. Upon binding its ligand, glucagon, the receptor initiates intracellular signaling cascades, primarily through G alpha (s) proteins, leading to increased cAMP production. This signaling is critical for stimulating gluconeogenesis and glycogenolysis in the liver. Expression data highlights its predominant and most significant role in [hepatocytes](/details-cell/CL0000182), consistent with its function as the primary mediator of glucagon's metabolic effects. Mutations in this gene are associated with conditions like hyperglucagonemia and have been investigated for their role in diabetes mellitus ([138033](https://omim.org/entry/138033)). ## Cellular Roles and Expression Landscape The expression profile of [GCGR](/details-gene/2642) firmly establishes its identity as a key receptor in metabolic and renal tissues. **Overall**, the gene's significance is highest by a substantial margin in [hepatocytes](/details-cell/CL0000182) (CSI: 5.59), including specific subpopulations like [periportal region hepatocytes](/details-cell/CL0019026) and [centrilobular region hepatocytes](/details-cell/CL0019029). This expression pattern underscores the liver's central role as the target organ for glucagon-mediated regulation of blood glucose. Beyond the liver, [GCGR](/details-gene/2642) shows significant expression in specific renal cell types, including the [renal alpha-intercalated cell](/details-cell/CL0005011) (CSI: 4.63), [kidney connecting tubule epithelial cell](/details-cell/CL1000768), and [kidney distal convoluted tubule epithelial cell](/details-cell/CL1000849). This suggests a secondary, but important, role for glucagon signaling in kidney physiology, potentially related to ion transport or blood pressure regulation. Additionally, its notable expression in [Mueller cells](/details-cell/CL0000636) of the retina suggests a specialized function within the central nervous system, possibly related to local energy metabolism or neuronal support. ## Pathways and Molecular Function The function of [GCGR](/details-gene/2642) is well-defined and centers on hormone-receptor signaling. As a member of the '[Glucagon-type ligand receptors](/details-pathway/R-HSA-420092)' ([R-HSA-420092](https://reactome.org/content/detail/R-HSA-420092)), its primary molecular function is '[Glucagon receptor activity](/details-pathway/GO:0004967)' ([GO:0004967](https://www.ebi.ac.uk/QuickGO/term/GO:0004967)), involving the specific binding of peptide hormones ([GO:0017046](https://www.ebi.ac.uk/QuickGO/term/GO:0017046)). Functionally, [GCGR](/details-gene/2642) is localized to the [plasma membrane](/details-pathway/GO:0005886) ([GO:0005886](https://www.ebi.ac.uk/QuickGO/term/GO:0005886)) and operates through the '[Adenylate cyclase-activating g protein-coupled receptor signaling pathway](/details-pathway/GO:0007189)' ([GO:0007189](https://www.ebi.ac.uk/QuickGO/term/GO:0007189)). This is a key component of '[Gpcr downstream signalling](/details-pathway/R-HSA-388396)' ([R-HSA-388396](https://reactome.org/content/detail/R-HSA-388396)), particularly '[G alpha (s) signalling events](/details-pathway/R-HSA-418555)' ([R-HSA-418555](https://reactome.org/content/detail/R-HSA-418555)). The biological consequences of this signaling are profound, directly contributing to '[Cellular response to glucagon stimulus](/details-pathway/GO:0071377)' ([GO:0071377](https://www.ebi.ac.uk/QuickGO/term/GO:0071377)) and playing an integral part in broad metabolic processes like '[Glucose homeostasis](/details-pathway/GO:0042593)' ([GO:0042593](https://www.ebi.ac.uk/QuickGO/term/GO:0042593)) and the '[Integration of energy metabolism](/details-pathway/R-HSA-163685)' ([R-HSA-163685](https://reactome.org/content/detail/R-HSA-163685)). Studies have detailed the molecular basis for its activation, regulation, and structure ([Link](https://doi.org/10.1038/nature12393), [Link](https://doi.org/10.1073/pnas.1206734109)). ## Research Directions Research on [GCGR](/details-gene/2642) has historically focused on its role in diabetes. Loss-of-function mutations are linked to alpha cell hyperplasia and hyperglucagonemia ([Link](https://doi.org/10.1097/mpa.0b013e3181b2bb03)), while other variants have shown heterogeneous associations with diabetes mellitus ([Link](https://doi.org/10.1007/bf00400589)). The expression profile provides avenues for new research into its extra-hepatic functions. Based on the available data, several testable hypotheses can be proposed: 1. The high significance of [GCGR](/details-gene/2642) in [renal alpha-intercalated cells](/details-cell/CL0005011) suggests that glucagon signaling directly modulates acid-base homeostasis in the kidney, potentially by regulating the activity of H+-ATPases or anion exchangers in these cells. 2. Given its expression in [Mueller cells](/details-cell/CL0000636), [GCGR](/details-gene/2642) may play a role in retinal neuroprotection during hypoglycemic stress by mobilizing local glycogen stores within these glial cells to support photoreceptor and neuronal function. To test the hypothesis regarding the renal role of [GCGR](/details-gene/2642), a key experiment could involve the use of kidney-specific or intercalated cell-specific Cre-Lox mouse models to knock out the *Gcgr* gene. Following knockout, mice could be subjected to metabolic acidosis challenges. The physiological response could be monitored by measuring blood pH, bicarbonate levels, and urinary ammonium excretion, while single-cell RNA sequencing of kidney tissue could be used to dissect the downstream transcriptional changes in intercalated cells lacking glucagon signaling. **Therapeutic Potential:** [GCGR](/details-gene/2642) is a well-established therapeutic target for type 2 diabetes and hyperglycemia. Because it mediates the glucose-elevating effects of glucagon, **inhibition** is the primary therapeutic strategy. As a cell surface receptor, it is highly druggable. The development of [GCGR](/details-gene/2642) antagonists, including small molecules and monoclonal antibodies, aims to block glucagon signaling in the liver, thereby reducing hepatic glucose production and lowering blood glucose levels in diabetic patients.

Genular Protein ID: 616623765

Symbol: GLR_HUMAN

Name: Glucagon receptor

UniProtKB Accession Codes:

P47871 Q2M3M5

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 2 DrugCentral 1 EMBL 5 EMDB 10 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 20 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 19 PDBsum 19 PIR 1 PRINTS 3 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 4 RefSeq 2 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 7507321

Title: Cloning and expression of a human glucagon receptor.

PubMed ID: 7507321

DOI: 10.1006/bbrc.1994.1046

PubMed ID: 8144028

Title: The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization.

PubMed ID: 8144028

DOI: 10.1016/0378-1119(94)90545-2

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 8020989

Title: Localization of the glucagon receptor gene to human chromosome band 17q25.

PubMed ID: 8020989

DOI: 10.1006/geno.1994.1179

PubMed ID: 9287038

Title: Role of the glucagon receptor COOH-terminal domain in glucagon-mediated signaling and receptor internalization.

PubMed ID: 9287038

DOI: 10.2337/diab.46.9.1400

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 16221670

Title: Conformational dimorphism of self-peptides and molecular mimicry in a disease-associated HLA-B27 subtype.

PubMed ID: 16221670

DOI: 10.1074/jbc.m508528200

PubMed ID: 22908259

Title: Molecular basis for negative regulation of the glucagon receptor.

PubMed ID: 22908259

DOI: 10.1073/pnas.1206734109

PubMed ID: 23863937

Title: Structure of the human glucagon class B G-protein-coupled receptor.

PubMed ID: 23863937

DOI: 10.1038/nature12393

PubMed ID: 27111510

Title: Extra-helical binding site of a glucagon receptor antagonist.

PubMed ID: 27111510

DOI: 10.1038/nature17414

PubMed ID: 28514451

Title: Structure of the full-length glucagon class B G-protein-coupled receptor.

PubMed ID: 28514451

DOI: 10.1038/nature22363

PubMed ID: 7589886

Title: A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus.

PubMed ID: 7589886

DOI: 10.1007/bf00400589

PubMed ID: 19657311

Title: Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.

PubMed ID: 19657311

DOI: 10.1097/mpa.0b013e3181b2bb03

PubMed ID: 25695890

Title: Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations.

PubMed ID: 25695890

DOI: 10.1210/jc.2014-4405

PubMed ID: 30032256

Title: Hypercalcemia in glucagon cell hyperplasia and neoplasia (Mahvash syndrome): a new association.

PubMed ID: 30032256

DOI: 10.1210/jc.2018-01074

PubMed ID: 30294546

Title: The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine.

PubMed ID: 30294546

DOI: 10.1016/j.ymgmr.2018.09.006

PubMed ID: 32677665

Title: Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders.

PubMed ID: 32677665

DOI: 10.1042/bcj20200235

Sequence Information:

  • Length: 477
  • Mass: 54009
  • Checksum: ADBB477C6267AE6E
  • Sequence:
    • MPPCQPQRPL LLLLLLLACQ PQVPSAQVMD FLFEKWKLYG DQCHHNLSLL PPPTELVCNR 
TFDKYSCWPD TPANTTANIS CPWYLPWHHK VQHRFVFKRC GPDGQWVRGP RGQPWRDASQ 
CQMDGEEIEV QKEVAKMYSS FQVMYTVGYS LSLGALLLAL AILGGLSKLH CTRNAIHANL 
FASFVLKASS VLVIDGLLRT RYSQKIGDDL SVSTWLSDGA VAGCRVAAVF MQYGIVANYC 
WLLVEGLYLH NLLGLATLPE RSFFSLYLGI GWGAPMLFVV PWAVVKCLFE NVQCWTSNDN 
MGFWWILRFP VFLAILINFF IFVRIVQLLV AKLRARQMHH TDYKFRLAKS TLTLIPLLGV 
HEVVFAFVTD EHAQGTLRSA KLFFDLFLSS FQGLLVAVLY CFLNKEVQSE LRRRWHRWRL 
GKVLWEERNT SNHRASSSPG HGPPSKELQF GRGGGSQDSS AETPLAGGLP RLAESPF