GLP1R gene

The GLP1R gene (GLP1R stands for: Glucagon Like Peptide 1 Receptor) is a protein-coding gene located on the short arm of chromosome 6p21.2. Alternative splicing of this gene leads to several transcript variants. Polymorphisms in this gene are associated with diabetes. The protein is an important target for drugs to treat type 2 diabetes and stroke (see semaglutide below). An important paralog of this gene is GCGR.

The GLP1R gene encodes a 7-transmembrane protein that acts as a receptor for the hormone glucagon-like peptide 1 (GLP-1), which stimulates glucose-induced insulin secretion. This receptor, which functions at the cell surface, is internalized in response to GLP-1 and GLP-1 analogs and plays an important role in the signaling cascades leading to insulin secretion. It also shows neuroprotective effects in animal models.

Diseases associated with GLP1R are insulinoma and hyperglycemia.

The signaling pathways associated with this gene include energy metabolism integration and GPCR downstream signaling, as well as G protein-coupled receptor activity and glucagon receptor activity.

GLP-1 receptors belong to the glucagon receptor family, which also includes glucagon, GLP-2, secretin, GHRH and GIP receptors. GLP-1 receptors are found both centrally and peripherally. GLP-1 receptors mediate the effects of the incretin axis (Underwood CR et al. 2010; Lau J et al. 2015; Thorens B et al. (1993). Ligand binding triggers the activation of a signaling cascade that leads to activation of adenylyl cyclase and increased intracellular cAMP levels (Underwood CR et al. 2010; Lau J et al. 2015, Graziano MP et al. 1993). The rezptor protein plays a role in the regulation of insulin secretion in response to GLP-1.

1. Graziano MP et al. (1993) Cloning and functional expression of a human glucagon-like peptide-1 receptor. Biochem Biophys Res Commun196:141-146.
2. Lau J et al. (2015) Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem 58:7370-7380.
3. Thorens B et al. (1993) Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 42):1678-1682.
4. Underwood CR et al. (2010) Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. J Biol Chem 285:723-730.