Receptor desensitization

Receptor desensitization can have differing overall effects on high- and low-efficacy agonists. 

Heterologous desensitization is a form of desensitization which does not require agonist binding of the receptor. Second messenger dependent kinases such as protein kinase A (PKA) and protein kinase C (PKC) are involved in this form of receptor desensitization. Heterologous desensitization simply depends on the overall kinase activity which is regulated by many different stimuli. 

Pharmocodynamic tolerance develops in response to continued application of drugs, by mechanisms that include reversible cellular adaptation processes, such as receptor desensitization, internalization and downregu-lation as well as changes in the activity and levels of other components of the receptor s signal transduction pathways. 

Tachyphylaxis is a loss of drug efficiency which develops in minutes or hours. Transmitter depletion and receptor desensitization are the basic mechanisms of this phenomenon. 

Many GPCRs contain one or more conserved cysteine residues within their C-terminal tails, which are modified by covalent attachment of palmitoyl or isoprenyl residues. The palmitoyl moiety is anchored in the lipid bilayer forming a fourth intracellular loop. There is evidence that palmitoylation of a GPCR is a dynamic process and may affect receptor desensitization. 

Taken together, the regulation of time course and extent of receptor desensitization and tolerance development involves complex cellular processes. Detailed understanding of the molecular mechanisms of receptor... 

Bohn LM, Gainetdinov RR, Lin FT et al (2000) p-Opioid receptor desensitization by (3-arrestin-2 determines morphine tolerance but not dependence. Nature 408 720-723... 

Receptor desensitization, internalization, and/or down-regulation may play a role in the development of tolerance to opioid receptor agonists (Clark et al. 

Bleich A, Gelkopf M, Weizman T, et al Benzodiazepine abuse in a methadone maintenance treatment clinic in Israel characteristics and a pharmacotherapeutic approach. Isr J Psychiatry Relat Sci 39 104-112, 2002 Bohn LM, Gainetdinov RR, Lin FT, et al Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408 720— 723, 2000... 

Anatoxin-a is the most potent and most stereospecific nicotinic acetylcholine receptor agonist thus far identified. It is also highly selective for nicotinic receptors over muscarinic receptors. The molecular parameters which influence the binding affinity, channel activation, channel blockade, and receptor desensitization are being studied. Modifications of the carbonyl and amine moieties can reduce or nearly eliminate the receptor agonist potency of the compounds and also determine the channel blocking characteristics. 

Bohn LM, Dykstra LA, Lefkowitz RJ, Caron MG, Barak LS (2004) Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery. Mol Pharmacol 66 106-112... 

Ferguson, S. S., Evolving concepts in G-protein-coupled receptor endocytosis the role in receptor desensitization and signaling, Pharmacol. Rev., 53(1), 1-24, 2001. 

Another complication is receptor desensitization. Desensitization of the nicotinic acetylcholine receptor is attributed to the receptor, especially in its activated form, changing spontaneously to a desensitized, inactive state. The following is a scheme incorporating all possible desensitized states of the receptor ... 

Chen et al. [62] have proposed that protein kinase C is involved in the fi receptor desensitization since activators of this enzyme potentate fi receptor uncoupling from the K+ channel. The fi receptor has consensus protein kinase C phosphorylation sites in its intracellular domains [8]. Arden et al. [88] have reported that morphine can induce the phosphorylation of the cloned fi receptor and Zhang et al. [64] have reported that activators of protein kinase C can induce the phosphorylation of the ft receptor. 

Prolonged 3 agonist treatment causes homologous desensitization in contrast to the heterologous nature of ft receptor desensitization. Furthermore, 3 agonists do not cause adaptive increases in adenylyl cyclase activity [74]. The lack of these compensatory responses may be one reason that 3 agonists do not cause addiction [99]. 

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