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Most peptides of interest act on G protein-coupled receptors (GPCR). Understanding what happens to the receptor after activation explains phenomena seen in the literature: loss of response with continuous exposure, differences between pulses and sustained exposure, and why the administration pattern matters as much as the dose.
Relevant families
- Class A (rhodopsin-like): receptors for ghrelin (GHS-R1a), melanocortins (MC1R–MC5R), oxytocin, kisspeptin (KISS1R).
- Class B (secretin): receptors for larger peptide ligands: GLP-1R, GIPR, glucagon receptor, GHRH-R, VPAC1/2. Their large extracellular domain captures the C-terminus of the peptide and the N-terminus activates the receptor («two-step» model).
From stimulus to signal
The activated receptor changes conformation and activates a heterotrimeric G protein. The most common pathways are Gs (↑ cAMP, typical of GLP-1R and GHRH-R), Gq (↑ intracellular Ca²⁺, typical of GHS-R1a and the oxytocin receptor) and Gi (↓ cAMP).
Desensitization: the receptor defends itself
Phosphorylation
Specific kinases (GRK) phosphorylate the activated receptor.
β-arrestin binding
It uncouples the receptor from the G protein: the signal fades within minutes.
Internalization
The receptor is removed from the membrane in vesicles.
Recycling or degradation
It returns to the surface (resensitization) or is degraded (downregulation).
Tachyphylaxis and exposure pattern
Continuous exposure to an agonist favors downregulation; pulsatile exposure allows time for recycling. The classic example is GnRH: in pulses it stimulates the reproductive axis and with continuous exposure it suppresses it, a principle used clinically with depot GnRH agonists. In the somatotropic axis, GH release is physiologically pulsatile, and that is one of the reasons why short-acting and long-acting analogs behave differently.
More exposure does not always mean more effect. For many GPCRs, the rhythm at which the agonist arrives determines whether the response is sustained or switches off.
Catalogue compounds mentioned in this lesson
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