GLP-1 receptor (revision 6)

The GLP-1 receptor (GLP1R) is a class B G-protein-coupled receptor and the molecular target of Glucagon-like peptide-1 and of every drug in the GLP-1 receptor agonist class. It belongs to the secretin-like receptor family, whose members are characterised by a large extracellular domain that captures the C-terminal portion of a peptide ligand before the ligand N-terminus engages the transmembrane bundle.^[1]

Activation couples principally to G_s, raising intracellular cAMP and activating protein kinase A and the exchange protein Epac2. In the pancreatic beta cell this cascade amplifies, but does not initiate, insulin exocytosis: the amplification requires a permissive rise in cytosolic calcium driven by glucose metabolism, which is the molecular basis of the glucose dependence that defines the class.^[2]

The receptor is expressed well beyond the pancreas, and the sites of expression explain much of the clinical profile of its agonists — gastric smooth muscle and enteric neurons for delayed emptying, the area postrema for nausea, and hypothalamic satiety circuits for reduced food intake.^[1]

GLP1R comprises an extracellular domain of about 130 residues, seven transmembrane helices and an intracellular C-terminal tail. Ligand binding follows the two-domain model characteristic of class B receptors: the C-terminal helix of the peptide is captured by the extracellular domain, which positions and concentrates the ligand, after which the peptide N-terminus inserts into a cavity formed by the transmembrane helices and drives the conformational change that couples to G protein.^[1]

Cryo-electron microscopy structures of the agonist-bound, G_s-coupled receptor have resolved the sharp kink in transmembrane helix 6 that accompanies activation. The structures also explain why the first eight residues of the peptide are indispensable while the C-terminal half tolerates extensive modification: acylation, PEGylation and fusion partners are all attached distal to the pharmacophore.^[3]

Small-molecule agonists bind a partially overlapping but distinct pocket, closer to the extracellular face of the transmembrane bundle, and do not require the extracellular-domain capture step. This is why an orally absorbable non-peptide agonist is chemically possible at all.^[1]