GCGR Gene (Glucagon Receptor): Function, Mutations, and Associated Diseases
The GCGR gene encodes the glucagon receptor, a key regulator of glucose homeostasis. This article covers its genomic context, protein function, expression patterns, associated diseases, and clinically relevant mutations.
Gene Information Card
| Symbol | GCGR |
|---|---|
| Full Name | Glucagon Receptor |
| Gene Type | Protein coding |
| Chromosomal Location | 17q25.3 |
| NCBI Gene ID | 2642 ncbi.nlm.nih.gov/gene/2642 |
| Ensembl ID | ENSG00000115646 |
| UniProt ID | P47871 |
| OMIM ID | 138033 |
| HGNC ID | 4192 |
| Aliases | GLR; MGC138246 |
Description
The GCGR gene encodes the glucagon receptor, a member of the class B G-protein coupled receptor (GPCR) family. This receptor is primarily expressed in the liver and kidney, where it binds the peptide hormone glucagon. Activation of the glucagon receptor plays a central role in glucose homeostasis by stimulating glycogenolysis and gluconeogenesis in the liver, thereby increasing blood glucose levels. The receptor is also involved in amino acid metabolism and insulin secretion regulation. Mutations in this gene can lead to hyperglycemia or hypoglycemia and are associated with specific metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Mahvash Disease | Biallelic loss-of-function mutations in GCGR lead to a lack of functional glucagon receptors. This causes hyperglucagonemia and pancreatic alpha-cell hyperplasia, which can progress to neuroendocrine tumors (glucagonomas). | OMIM #231060; PMID: 25683120 |
| Type 2 Diabetes Mellitus (T2DM) | Common genetic variants in GCGR are associated with altered fasting plasma glucose levels and an increased risk of T2DM. These variants may affect receptor expression or signaling efficiency, contributing to impaired glucose regulation. | GWAS Catalog; PMID: 20081858 |
| Glucagonoma | While glucagonomas are often sporadic, somatic mutations in the GCGR gene have been identified in some pancreatic neuroendocrine tumors. These mutations may contribute to tumorigenesis by disrupting normal receptor signaling. | COSMIC; PMID: 28270521 |
| Hyperglycemia | Loss-of-function mutations in GCGR can impair the body's ability to respond to glucagon, leading to a reduced capacity to raise blood glucose levels. However, the primary clinical manifestation is hyperglucagonemia, with glucose levels often being normal or slightly low. | OMIM #231060 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 20.1 | High |
| Kidney | 8.5 | Medium |
| Adipose Tissue | 2.3 | Low |
| Pancreas | 1.2 | Low |
| Small Intestine | 0.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (Liver) | 15.3 | High expression; used for studying glucagon signaling. |
| HEK 293 (Embryonic Kidney) | 6.7 | Moderate expression; commonly used for transfection studies. |
| A549 (Lung) | 0.5 | Low expression; not a primary site of action. |
| MCF7 (Breast) | 0.2 | Very low expression; not physiologically relevant. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.79G>A (p.Gly27Arg) | Missense | Rare | Loss-of-function; impairs receptor trafficking to the cell surface. |
| c.1100T>C (p.Phe367Ser) | Missense | Rare | Loss-of-function; disrupts ligand binding and receptor activation. |
| c.1243C>T (p.Arg415Ter) | Nonsense | Rare | Loss-of-function; leads to a truncated, non-functional receptor. |
| c.451G>A (p.Gly151Ser) | Missense | Rare | Loss-of-function; affects receptor signaling and expression. |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic GCGR mutations are loss-of-function. They impair receptor expression, ligand binding, or downstream signaling. Biallelic loss-of-function causes Mahvash disease, characterized by alpha-cell hyperplasia and hyperglucagonemia.
Gain of Function (GOF)
Gain-of-function mutations in GCGR are extremely rare and not well-documented. Such mutations would theoretically lead to increased glucagon signaling, potentially causing hyperglycemia, but no definitive pathogenic gain-of-function variants have been clinically validated.
Dominant Negative (DN)
A dominant-negative effect has not been clearly established for GCGR mutations. Since the receptor functions as a monomer, a single mutant allele is unlikely to exert a dominant-negative effect. The disease inheritance pattern is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
| • G protein-coupled receptor activity | • glucagon receptor activity |
| • peptide hormone binding | • plasma membrane |
| • integral component of plasma membrane | • adenylate cyclase-activating G protein-coupled receptor signaling pathway |
| • glucose homeostasis | • response to glucagon |
| • positive regulation of glycogenolysis | • positive regulation of gluconeogenesis |
Pathways
• Glucagon signaling pathway
• GPCR downstream signaling
• cAMP-mediated signaling
• Regulation of glycogen metabolism
• Type II diabetes mellitus
Protein Summary
The glucagon receptor (GCGR) is a 493-amino acid protein with a molecular weight of approximately 55 kDa. It is a class B G-protein coupled receptor characterized by a large N-terminal extracellular domain involved in ligand binding, a seven-transmembrane helical domain, and an intracellular C-terminal tail. Upon glucagon binding, the receptor undergoes a conformational change that activates the associated Gs protein, leading to the activation of adenylate cyclase and an increase in intracellular cAMP levels. This triggers a signaling cascade that activates protein kinase A (PKA), which in turn phosphorylates key enzymes involved in glucose metabolism, such as glycogen phosphorylase kinase and CREB. The receptor is also subject to post-translational modifications, including glycosylation and phosphorylation, which regulate its trafficking and signaling.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GCGR Knockout HEK293 Cell Line | EDJ-KQ4690 | Human | 2642 | Details Get a Quote |
| GCGR Knockout HeLa Cell Line | EDJ-KQ53315 | Human | 2642 | Details Get a Quote |
| GCGR Knockout A-549 Cell Line | EDJ-KQ61798 | Human | 2642 | Details Get a Quote |
| GCGR Knockout HCT 116 Cell Line | EDJ-KQ70283 | Human | 2642 | Details Get a Quote |
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