Homologous desensitization

Homologous desensitization is a form of desensitization which is mediated by agonist-induced activation of the same receptor. G-protein-coupled receptor kinases (GRKs) and arrestins are involved in this process, which leads to an uncoupling of the receptor from its G protein. 

HMG CoA-Reductase HMG-CoA-Reductase Inhibitors Homologous Desensitization Homologous Proteins Homologous Recombination Homology Modeling Hormonal Contraceptives Hormone Replacement Therapy (HRT)... 

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]. 

Phosphorylation of the P-adrenergic receptor by PARK, like its phosphorylation by the cAMP-dependent enzyme, represents an example of negative feedback. However, unlike phosphorylation by cAMP-dependent protein kinase, phosphorylation by PARK represents an example of homologous desensitization only the P-adrenergic receptor would be affected in this process and, moreover, only those receptor molecules occupied by ligand would be affected. 

Sallese, M., Salvatore, L., D Urbano, E., et al. (2000) The G protein-coupled receptor kinase GRK4 mediates homologous desensitization of metabotropic glutamate receptor 1. FASEB J. 14, 2569-2580. 

Lewis, M. M., Watts, V. J., Lawler, C. P., Nichols, D. E., and Mailman, R. B. (1998) Homologous desensitization of the D dopamine receptor efficacy in causing desensitization dissociates from both receptor occupancy and functional potency. J. Pharmacol. Exp. Ther. 286, 345-353. 

There are two major categories of desensitization of responses mediated by G protein-coupled receptors. Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist. Heterologous desensitization refers to the process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question. 

A major mechanism of desensitization that occurs rapidly involves phosphorylation of receptors by members of the G protein-coupled receptor kinase (GRK) family, of which there are seven members. Specific adrenoceptors become substrates for these kinases only when they are bound to an agonist. This mechanism is an example of homologous desensitization because it specifically involves only agonist-occupied receptors. 

Aronica E, Dell Albani P, Condorelli DF et al (1993) Mechanisms underlying developmental changes in the expression of metabotropic glutamate receptors in cultured cerebellar granule cells homologous desensitization and interactive effects involving N-methyl-D-aspartate receptors. Mol Pharmacol 44 981-9... 

Lewis MM, Watts VJ, Lawler CP, Nichols DE, Mailman RB. Homologous desensitization of the D1A dopamine receptor efficacy in causing desensitization... 

An ITH injection of [D-Ala2]deltorphin II produces an acute antinociceptive tolerance [128], Concomitant pretreatment with lower doses of the PKC inhibitor calphostin C markedly prevents the development of acute tolerance to the ITH-administered [D-Ala2]deltorphin II-induced antinociception. On the other hand, the PKA inhibitor KT5720, has no effect on the development of acute tolerance to [D-Ala2]deltorphin II antinociception [128], It is therefore likely that PKC, but not PKA, plays an important role in the process of homologous desensitization of the spinal delta opioid receptor-mediated antinociception. 

An important concept to appreciate regarding receptors is that they are not static, stand-alone components of a cell. On the contrary, they are an integral part of the overall homeostatic balance of the body. For example, receptors can become desensitized upon continuous exposure to an agonist. When desensitization involves a specific class of agonists it is referred to as homologous desensitization. If response is reduced by disparate classes of drugs, the term heterologous desensitization is applied. 

Winkler JD, Sarau HM, Foley JJ et al. (1988) Leukotriene B4-induced homologous desensitization of calcium mobilization and phosphoinositide metabolism in U-937 cells. J Pharmacol Exp Ther 246 204-210... 

Transfected TP-a and TP-P receptors in CHO cells demonstrated different patterns of homologous desensitization. TP-a receptors, overexpressed in fibroblasts, decreased in number, as did native platelet receptors, following 24 hour exposure to I-BOP, but TP-P receptors increased following similar long-term exposure to I-BOP (160). Activation of PKC uncoupled calcitun mobilization from TP-P receptors to a greater extent than from TP-a receptors (160). These differences cannot be attributed to differences in phosphorylation, since both isoforms transfected into HEK cells were phosphorylated similarly on agonist stimulation (60). 

Okwu AK, Ullian ME, Hahishka PV. Homologous desensitization of human thromboxane Aj/prostaglandin Hj receptors. J Pharmacol Exp Ther 1992 262 238-45... 

Sakai K, Nakahata N, Ono H, Yamamoto T, CMiizumi Y. Homologous desensitization of thromboxane A, receptOT in 1321N1 human astrotyhana cells. J niarmacol Exp Ther 1996 276 829-36... 

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