2.4 Receptor inactivation
As with all signalling components, receptors need to be switched off as well as on. Receptor inactivation can operate in several ways including removal of the ligand by degradation or sequestration, and desensitization of the target cell.
Binding of a ligand to its receptor is a reversible process, as the ligand will ultimately dissociate from the receptor and may be degraded. Acetylcholine is a good example of a signal regulated in this way; it is degraded by the enzyme cholinesterase within milliseconds of its release from neuron terminals.
Ligand removal may also occur by sequestration following binding to proteins other than its normal receptor (these may be decoy receptors or extracellular proteins). ‘Decoy receptors’ are cell surface receptors that bind the ligand but do not convey the signal onward in the pathway (for example, truncated RTKs that lack the intracellular kinase domain). Similarly, soluble extracellular proteins containing ligand-binding domains may also sequester the ligand. In both cases, the effect of the extracellular signal is neutralized prior to receptor binding.
If the ligand cannot be degraded or sequestered, the target cell may, after prolonged activation, become desensitized. Desensitization can occur in several ways, the principal ones being inactivation of the receptor (blocking its interaction with downstream signalling components), sequestering the receptor into endocytic vesicles (from which it can be recycled back onto the plasma membrane), or ultimately degrading the receptor in lysosomes. These mechanisms of receptor desensitization usually function in sequence, and progression from one stage to another can depend on factors such as ligand concentration. Activated GPCRs can be desensitized when they are phosphorylated by different protein kinases. The phosphorylated receptor then binds to a cytosolic protein called arrestin, forming a complex that both blocks any interaction with downstream signalling molecules and couples the receptor to clathrin-coated pits , inducing receptor-mediated endocytosis. Another example of desensitization induced by binding of a cytosolic protein to the receptor is provided by c-Cbl. It binds to phosphotyrosine residues of certain activated RTKs via its SH2 domains, thereby promoting the association of the receptor–Cbl complex with ubiquitin. The receptors are then sequestered and degraded via the ubiquitin–proteasome pathway.