GLP-1 receptor (revision 9)
Old revision·21:57, 17 Sep 2024·ArcuateArt
| GLP-1 receptor | |
|---|---|
Extracellular domain capture followed by insertion of the peptide N-terminus into the transmembrane bundle. | |
| Symbol | GLP1R |
| Family | Class B1 secretin-like GPCR |
| Endogenous ligand | Glucagon-like peptide-1 |
| Signalling | |
| Principal coupling | Gs → adenylyl cyclase → cAMP |
| Secondary | Gq, β-arrestin recruitment |
| Desensitisation | GRK phosphorylation, internalisation |
| Topic infobox · conventions | |
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 Gs, 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]
Structure and ligand engagement
[edit]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, Gs-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]
References
- ^ a b c d de Graaf C, Donnelly D, Wootten D, et al. "Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes." Pharmacological Reviews 68(4):954–1013 (2016). DOI:10.1124/pr.115.011395. PMID 27630114.
- ^ Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). PMID 29617641.
- ^ Zhang Y, Sun B, Feng D, et al. "Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein." Nature 546(7657):248–253 (2017). DOI:10.1038/nature22394. PMID 28492058.