Glucagon-like peptide-1 receptor (GLP-1R)

The Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that is a major therapeutic target for type 2 diabetes and obesity. It is a transmembrane protein with seven alpha-helical transmembrane domains, an extracellular N-terminus, and an intracellular C-terminus. It features a large N-terminal extracellular domain (ECD) characteristic of class B GPCRs. GLP-1R mediates the actions of the peptide hormone GLP-1, released from intestinal L cells. Upon GLP-1 binding, it triggers potentiation of glucose-induced insulin secretion, increased insulin expression, prevention of β-cell apoptosis, promotion of new β-cells, reduced glucagon secretion, slowed gastric emptying, promoted satiety, and improved glucose disposal. Molecular signaling involves Gs coupling, adenylate cyclase activation, cAMP production, and downstream activation of PKA and other pathways, amplifying insulin exocytosis and activating prosurvival pathways. GLP-1R is expressed in various tissues including pancreas, brain, heart, kidney, stomach, and lungs, indicating broader physiological importance. Therapeutic agonists (GLP-1RAs) are used clinically to manage diabetes and obesity, offering cardiovascular and potentially neurological benefits by targeting this receptor.

GLP-1 receptor agonists bind to and activate the GLP-1R. Receptor activation involves a two-domain model where the peptide's C-terminus first binds the receptor's N-terminal ECD, followed by the peptide's N-terminus binding the receptor's core domain. This activation leads to conformational changes, engagement with the Gs subunit, activation of adenylate cyclase, increased cAMP production, activation of PKA and other effectors, amplification of insulin secretion, and activation of prosurvival pathways. Continued stimulation results in receptor phosphorylation, β-arrestin recruitment, internalization, and endosomal signaling. GLP-1RAs overcome the rapid degradation of endogenous GLP-1.