Receptor Internalisation
The process by which a cell takes receptor-ligand complexes from the surface into the cell interior. Receptor internalisation removes receptors from the surface, reducing cellular responsiveness. This mechanism contributes to desensitisation and downregulation during sustained peptide drug exposure.
Technical Context
Following agonist binding, GPCRs undergo: (1) desensitisation — GRK phosphorylation of the receptor → beta-arrestin binding → uncoupling from G-proteins (seconds-minutes), (2) internalisation — beta-arrestin recruits clathrin and AP-2 → clathrin-coated pit formation → dynamin-mediated vesicle scission → endosome formation (minutes), (3) intracellular sorting — either recycling to the surface (rapid recycling via Rab4/11 endosomes → receptor resensitisation) or degradation (late endosomes → lysosomes → receptor downregulation). The balance between recycling and degradation determines whether receptor number recovers (resensitisation) or declines (downregulation). For GnRH receptors (which lack cytoplasmic tails), internalisation follows a non-classical pathway — the GnRH receptor does not bind beta-arrestin efficiently, so internalisation is slower and relies on other mechanisms. This unusual receptor biology contributes to the unique pharmacology of GnRH agonist therapy.