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Receptor agonist

A receptor agonist is a ligand that binds a receptor and activates it, so that binding is linked to a response in the cell. Receptors are the molecules whose function is chemical recognition: they recognise endogenous chemical signals, and signal transduction links ligand binding to a response.[1],[2],[3]

What is a receptor?

A review by Rang describes chemical signalling as the main mechanism by which biological function is controlled, and chemical recognition as the function of receptors. The receptor concept arose early in the 20th century and receptors were later isolated and cloned, to the point of a virtually complete catalogue of the receptors present in the genome. Rang notes that some simple quantitative rules of receptor theory are still useful, while current work concentrates on the pathways that link receptors to responses.[1]

What does receptor activation look like in a peptide receptor?

Mayo reported in 1992 the cloning of a pituitary receptor for growth hormone-releasing hormone (GHRH). Membranes from cells expressing it bound GHRH with high affinity and specificity, and GHRH stimulated intracellular cAMP production in those cells.[2]

Zhang and colleagues reported in 2017 a cryo-electron microscopy structure of the peptide-activated GLP-1 receptor in complex with the G protein Gs. The peptide is clasped between the receptor's N-terminal domain and its transmembrane core, and activation is accompanied by a sharp kink in transmembrane helix 6.[3]

In that structure, the kink in transmembrane helix 6 pivots its intracellular half outward to accommodate the alpha-5 helix of the Ras-like domain of Gs. The authors present the result as a structural framework for understanding class B receptor activation through hormone binding.[3]

What is a G protein-coupled receptor?

The GHRH receptor contains seven potential membrane-spanning domains, which Mayo describes as a hallmark of G protein-coupled receptors. The GLP-1 receptor is a class B G protein-coupled receptor that signals primarily through the stimulatory G protein Gs.[2],[3]

Mayo reported that the GHRH receptor is homologous to previously identified receptors for secretin and vasoactive intestinal peptide, ligands that are related to GHRH.[2]

How do antagonists and inverse agonists differ from agonists?

Kenakin describes efficacy as having a direction. Competitive antagonists with negative efficacy show inverse agonism in receptor systems that are constitutively active; without constitutive activity, inverse agonists behave as simple competitive antagonists.[4]

In a survey of 105 articles covering 380 antagonists at 73 G protein-coupled receptor targets, Kenakin found 322 inverse agonists and 58 neutral antagonists.[4]

Can one peptide act at more than one receptor?

Yes. Chang and colleagues describe unimolecular dual agonists of the glucagon receptor and the GLP-1 receptor, and report a cryo-electron microscopy structure of the glucagon receptor bound to one such peptide.[5]

That peptide, peptide 15, is described as having potency equivalent to the cognate peptide agonists at both receptors. Compared with glucagon, it showed reduced interaction with the first extracellular loop and the extracellular end of transmembrane segment 1 of the glucagon receptor.[5]

Limitations

Whether a ligand appears as an agonist, antagonist or inverse agonist depends on the assay. Kenakin notes that inverse agonism can only be observed in an appropriate assay, where constitutive receptor activity is present.[4]

A structure or a cell assay shows how a ligand acts on a receptor in that system. It does not show what the ligand does in a whole organism.[1]

Compound profiles

Compound profiles that record receptor agonist activity for the compound.

References

  1. Rang HP. The receptor concept: pharmacology's big idea. Br J Pharmacol. 2006;147 Suppl 1:S9-S16. PMID 16402126 · DOI 10.1038/sj.bjp.0706457 · PMC1760743
  2. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992;6(10):1734-1744. PMID 1333056 · DOI 10.1210/mend.6.10.1333056
  3. Zhang Y, Sun B, Feng D, et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature. 2017;546(7657):248-253. PMID 28538729 · DOI 10.1038/nature22394 · PMC5587415
  4. Kenakin T. Efficacy as a vector: the relative prevalence and paucity of inverse agonism. Mol Pharmacol. 2004;65(1):2-11. PMID 14722230 · DOI 10.1124/mol.65.1.2
  5. Chang R, Zhang X, Qiao A, et al. Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide. J Biol Chem. 2020;295(28):9313-9325. PMID 32371397 · DOI 10.1074/jbc.RA120.013793 · PMC7363120