GLP-1 receptor: difference between revisions
Diff·revision 9 → 10·04:49, 6 Oct 2024
Difference between revision 9 and revision 10 of GLP-1 receptor. 6 lines changed; the page grew by 997 bytes.
| Revision 9 — 21:57, 17 Sep 2024 ArcuateArt (talk) split §Physiology from §Pharmacological exploitation 3,867 bytes +153 | Revision 10 — 04:49, 6 Oct 2024 GIP_Genoveva (talk) typo 4,864 bytes +997 | ||
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| 25 | 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.{{r|graaf2016}} | 25 | 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.{{r|graaf2016}} |
| 26 | 26 | ||
| + | 27 | == Signalling and receptor bias == | |
| + | 28 | Beyond G<sub>s</sub>, the activated receptor recruits β-arrestin, which terminates G-protein signalling and initiates internalisation. Agonists differ in the ratio of cAMP accumulation to β-arrestin recruitment they produce, a phenomenon described as [[Receptor bias|biased agonism]].{{r|jones2018}} | |
| + | 29 | ||
| + | 30 | Bias has been proposed as a design lever: an agonist that produces sustained cAMP with reduced β-arrestin recruitment internalises the receptor less, maintains surface expression, and might therefore sustain insulin secretion better over prolonged exposure. Evidence for this in humans is indirect, and the ''in vitro'' bias factors reported for marketed agonists have not been shown to predict clinical differences.{{r|jones2018}} | |
| + | 31 | ||
| 27 | == References == | 32 | == References == |
| 28 | {{reflist}} | 33 | {{reflist}} |
| 29 | <ref name="graaf2016">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.</ref> | 34 | <ref name="graaf2016">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.</ref> |
| 30 | <ref name="zhang2017">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.</ref> | 35 | <ref name="zhang2017">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.</ref> |
| + | 36 | <ref name="jones2018">Jones B, Buenaventura T, Kanda N, et al. "Targeting GLP-1 receptor trafficking to improve agonist efficacy." ''Nature Communications'' 9:1602 (2018). DOI:10.1038/s41467-018-03941-2. PMID 29686245.</ref> | |
| 31 | <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> | 37 | <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> |
| 32 | 38 |