• The rapid signal attenuation in response to stimulation of cells by agonists.
• In other words decrease in the response of a drug due to frequent administrations.
• Continuous stimulation of cells with agonists generally results in a state of desensitization .
• also referred to as adaptation, refractoriness, or down-regulation .
• The term tolerance is conventionally used to describe more gradual decrease in response of drug which takes days or weeks to develop.
-> After exposure to an agonist, the initially maximum response is seen. -> Now if we continue to administer agonist it shows decrease in response due to desensitization of receptors. -> Removal of the drug for a more extended period allows the cell to recover its capacity to respond.
-> When agonist is administered continuously,desensitization of the receptor results ; when agonist falls below a certain threshold,the system again becomes sensitive. -> E.G. Think of whathappens to your visual transduction system when you walk from bright sunlight into a darkened room or from darkness into the light. Lehninger principles of biochemistry 4th Edition pg.427
Five ways by which target cells can become desensitized to a signal molecule. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2792
Many factors can give rise to phenomenon of desensitization.
-> desensitisation is often rapid and pronounced with ionic receptors.
-> At the neuromuscular junction, the desensitised state is caused by conformational change in the receptor, which will result in the tight binding of the agonist molecule without the opening of the ionic channel.
-> Phosphorylation of intracellular regions of the receptor protein is a second, slower mechanism by which ion channels become desensitised .
Acetylcholine (ACh) at the frog motor endplate. -> Initially brief depolarisations (upward deflections) are produced by short pulses of ACh delivered from a micropipette. -> A long pulse (horizontal line) causes the response to decline, which shows the ionic receptor desensitisation, and it recovers with a similar time course. In Nut Shell Conformational change in receptor leads to receptor desensitisation.
-> Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface , as a result of internalisation of the receptors.
-> β-Adrenoceptors of rat glioma cells in tissue culture. Isoprenaline (1μmol/l) was added at time zero, the response and β-adrenoceptor density measured at intervals. During the early phase, the response (blue line) declines with no change in receptor density (red line). Later, the response declines further concomitantly with disappearance of receptors from the membrane by internalisation. The green and orange lines show the recovery of the response and receptor density after the isoprenaline is washed out. In Nut Shell Loss of receptor due to intenalisation lead to receptor desensitisation.
General Mechanism of Agonist mediated Desensitization
Phosphorylation of the receptor by specific GPCR kinases (GRKs) plays a key role in triggering rapid desensitization.
1. Phosphorylation of agonist-occupied GPCRs by GRKs
facilitates the binding of cytosolic proteins termed arrestins to the receptor.
2. This results in uncoupling of G protein from the receptor.
3. Now β-arrestins recruit proteins such as PDE4 (which limits cyclic AMP signaling), and others such as clathrin and β 2- adaptin , this all will promot sequestration of receptor from the membrane (internalization).
Steps involved in Agonist-induced internalization of GPCRs.
1. Agonist activation of many GPCRs results in receptor phosphorylation by GPCR-specific kinases (GRK).
2. The phosphorylated GPCR recruits β-arrestin , which initiates receptor targeting to clathrin-coated pits.
3. Endosomal acidification permits dissociation of the agonist.
4. The GPCR is dephosphorylated by a G-protein-coupled receptor specific phosphatase (GRP).
5. Internalized receptors can recycle to the cell surface or are degraded in lysosomes.
Encyclopedic Reference of Molecular Pharmacology pg. no. 913
desensitization of β -receptor due to continuous exposure to epinephrine.
Desensitization of the β –adrenergic receptor in the continued presence of epinephrine. This process is mediated by two proteins: - Β - adrenergic protein kinase (ARK) & β -arrestin (arr ; arrestin 2). Lehninger principles of biochemistry 4th Edition pg.440
• Researchers studied 30 first year medical students during final examination week and one month earlier. Platelet a2 receptor binding was measured using 3H-yohimbine.
• During final examination week, platelet α 2-receptor binding affinity was significantly reduced, while levels of plasma catecholamines and anxiety were significantly increased, compared with the earlier period.
• This study shows that stress can also play a role in induction of the desensitization.
β -arrestin 1 and β -arrestin 2 are well known negative
regulators of G-protein-coupled receptor (GPCR)signaling.
1) They promotes GPCR internalization, thus causing desensitization. or
2) They also function as scaffold proteins
that interact with several cytoplasmic proteins.
3) Recent work has also revealed that, in response to activation of certain GPCRs , β -arrestins translocate from the cytoplasm to the nucleus and associate with various transcription cofactors such as p300 and cAMP-response element-binding protein (CREB) to promote transcription.
http://jcs.biologists.org/cgi/reprint/120/2/213 Journal of Cell Science