1.4.5 Desensitisation

Radioligand binding assays showed that the concentration of α and β receptors within one tissue is very variable. Several hormones, medicines, physiologic and pathologic situations influence the number of these receptors (Table 1.7). Desensitisation means, that physiological response wanes over time despite the presence of a stimulus of constant intensity. Three major processes have been postulated to contribute to agonist induced desensitisation  [88]:

• A rapid (seconds to minutes) uncoupling event renders the receptor less able to activate the G_s protein. The major mediator for this process appears to be receptor phosphorylation.
• A second mechanism of desensitisation is receptor sequestration. This is a rapid (minutes) agonist-promoted internalisation of receptors to a cellular compartment distinct from the plasma membrane, but wherein the receptors are still detectable using hydrophobic radioligands. Upon removal of agonist, these receptors are thought to be recycled to the cell surface in a fully functional state. An alternative hypothesis postulates that the receptors are not physically translocated within the cell but are sequestrated in the plasma membrane in a conformation that does no longer support the binding of hydrophilic ligands.
• Prolonged treatment (hours) of cells with agonists results in receptor-downregulation, whereby the total cellular adrenoceptor binding is decreased. Under certain experimental conditions, the reappearance of receptor binding following removal of agonist requires de novo protein synthesis.

© 2001 Alexander Binder