Activated GPCRs can be desensitized when they are phosphorylated by different protein kinases. These mechanisms of receptor desensitization usually function in sequence, and progression from one stage to another can depend on factors such as ligand concentration. 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. If the ligand cannot be degraded or sequestered, the target cell may, after prolonged activation, become desensitized. In both cases, the effect of the extracellular signal is neutralized prior to receptor binding. Similarly, soluble extracellular proteins containing ligand-binding domains may also sequester the ligand. ‘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). Ligand removal may also occur by sequestration following binding to proteins other than its normal receptor (these may be decoy receptors or extracellular proteins). 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.

Receptor inactivation can operate in several ways including removal of the ligand by degradation or sequestration, and desensitization of the target cell.īinding of a ligand to its receptor is a reversible process, as the ligand will ultimately dissociate from the receptor and may be degraded. As with all signalling components, receptors need to be switched off as well as on.

Cell signal