Often the effect of a drug gradually diminishes when given continuously or repeatedly; the term used to describe this phenomenon is desensitisation and often develops in the course of a few minutes.
Desensitisation is defined as a loss of functional response that can occur in adrenergic receptors exposed to continuous agonist stimulation. Desensitisation can be described as long or short term. Short-term desensitisation is normally associated with phosphorylation of receptor protein followed by uncoupling from the signal pathway. Long-term desensitisation usually involves regulation of gene expression of the receptor and other proteins in the signaling pathway.
Short-term desensitisation involves the phosphorylation of the receptor by the enzymes Protein Kinase A (PKA) or G-protein Receptor Kinase (GRKs). This process has been extensively researched for the b2 adrenoceptor and concerns the phosphorylation of serine and threonine residues in the carboxy terminus tail of the agonist occupied receptor by GRKs. Only agonist occupied receptors are substrates for these particular enzymes therefore making this process homologous and dependent on high receptor occupancy. Agonist occupied receptors activate the a sub-unit of Gs-protein which converts GDP to GTP and uncouples from the bg sub-units to activate adenylate cyclase. He bg sub-units are thought to bind to the GRKs that then phosphorylate the receptor. The newly phosphorylated receptor then acts as a receptor for the cytostolic protein b-arrestin, which then binds to the third intracellular loop and the carboxy tail of the receptor and uncouples it from the Gs-protein.
Heterologous desensitisation is believed to involve the phosphorylation of b-ARs by PKA. Substances which increase intracellular levels of cAMP levels either by receptor activation, e.g. b-agonists, or by direct activation of adenylate cyclase, e.g. forskolin or cell permeable cAMP analogues (dibutyryl cAMP) all cause phosphorylation and subsequent uncoupling of b2 -AR from the signaling pathway.
The b2 adrenoceptors contains two PKA phosphorylation sites, mutations of these sites results in a lack of phosphorylation or desensitisation to isoprenaline
In contrast to the b1 and b2 AR, the b3-AR has a much shorter carboxy terminus and has fewer potential phosphorylation sites. In accordance with this b3 AR are resistant to desensitisation by mechanisms involving phosphorylation. Formation of a chimeric b3 receptor with a b2 carboxy terminus tail produced a b3 receptor with an increased number of GRK phosphorylation sites that partially desensitised after agonist exposure.