Desensitisation
A reduction in receptor responsiveness following prolonged or repeated agonist exposure, even though the agonist remains bound to the receptor. Desensitisation can occur through receptor phosphorylation, uncoupling from G-proteins, or internalisation. It is a key mechanism in GnRH agonist therapy.
Technical Context
Desensitisation occurs in two phases: homologous desensitisation (specific to the activated receptor, mediated by G-protein coupled receptor kinases/GRKs and beta-arrestins) and heterologous desensitisation (affecting multiple receptor types, mediated by protein kinase A/C). GRKs phosphorylate the agonist-occupied receptor, promoting beta-arrestin binding, which sterically blocks G-protein coupling and targets the receptor for internalisation via clathrin-coated pits. For GnRH agonists, both desensitisation and subsequent downregulation contribute to the therapeutic suppression of gonadotropin release. The rate and degree of desensitisation vary by receptor type and cell type.