Figure 4.
The manner of action on the glucagon-like peptide-1 (GLP-1) receptor differs between native GLP-1 and LY3502970 (orforglipron). The GLP-1 receptor belongs to the class B G-protein coupled receptor (GPCR) family. Schematic explanations A to D illustrate the classic model of G-protein-mediated activation and β-arrestin-related desensitization in GLP-1 receptor agonism by native GLP-1, while E demonstrates the biased agonism of LY3502970 on the GLP-1 receptor. (A) Inactive state of the GLP-1 receptor. (B) Activated GLP-1 receptor with attached GLP-1, leading to the substitution of guanosine diphosphate (GDP) with guanosine triphosphate (GTP) on the α subunit of the Gs protein (Gαs). (C) Gα dissociates from the G-protein and stimulates adenyl cyclase (AC), converting adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and resulting in elevated cAMP levels. Simultaneously, the C-terminal tail of the GLP-1 receptor is phosphorylated by G protein-coupled receptor kinase (GRK), allowing β-arrestin to bind to the GLP-1 receptor, forming a complex. (D) Internalization of the GLP-1 receptor by β-arrestin. (E) The biased agonism of LY3502970 primarily proceeds through the cAMP pathway with reduced β-arrestin recruitment.58 This biased agonism is also exhibited by TT-OAD2, another orally administered nonpeptidic GLP-1R agonist compound.59 However, it is important to note that GPCR signaling is significantly more complex. GPCRs can couple with various G-protein families, activate them differentially depending on conditions, and also engage non-G-protein-related signaling pathways.60