Adrenergic receptor desensitization

Lohse, M. J., Benovic, J. L., Caron, M. G., and Lefkowitz, R. J. (1990) Multiple pathways of rapid beta 2-adrenergic receptor desensitization. Delineation with specific inhibitors. J. Biol. Chem. 265, 3202-3211. 

Quin, F., Yan, C., Patel, R., Liu, W., and Dong, E. 2006. Vitamin C and E attenuate apoptosis, p-adrenergic receptor desensitization, and sarcoplasmic reticular Ca2+ ATPase dowmegulation after myocardial infarction. Free Radic. Biol. Med. 40 1827-1842. 

Lin F, Wang H, Malbon CC. Gravin-mediated formation of signaling complexes in p2-adrenergic receptor desensitization and resensitization. J Biol Chem 2000 275 19,025-19,034. 

Multiple pathways of rapid beta 2-adrenergic receptor desensitization. Delineation with specific inhibitors. J Biol Chem 265 3202-3211... 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Adrenergic receptor agonists are also used to treat premature labour by causing uterine relaxation. Fenoterol and ritodrine are frequently used. The effectiveness of long-term tocolysis is controversial, since both desensitization of the receptors and the symptomatic nature of this treatment may limit their effects to 1-2 days according to one large study. 

Regulation of neurotransmitter receptors the p-adren-ergic receptor. This receptor, of which three subtypes have been cloned, mediates many of the effects of norepinephrine and epinephrine in the brain and peripheral tissues. One of the dramatic features of P-adrenergic receptor function is its rapid desensitization in response to agonist stimulation. It is now known that one important mechanism for this desensitization is phosphorylation of the receptor both by PKA and by a receptor-associated protein kinase, PARK (also called GRK2 Fig. 23-6). 

Phosphorylation of the -adrenergic receptor by PKA can be viewed as a classical example of negative feedback activation of the receptor stimulates intracellular cascades that feed back to reduce further receptor activation. Phosphorylation of the receptor by PKA could also mediate heterologous desensitization of the receptor any neu-rotransmitter-receptor system that works through cAMP would be expected to stimulate P-adrenergic receptor phosphorylation via PKA and lead to receptor desensitization. This is one mechanism by which one neurotrans-mitter-receptor system can affect another. 

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. 

In case of the P -adrenergic receptor, phosphorylation of serine and threonine residues in the carboxyl tail can be shown to be involved in desensitization and internalization (141,156). Other GPCRs—such as the p- and 5-opioid receptors... 

The residues required for internalization, like those implicated in desensitization motifs, do not always meet the requirements for putative sites of kinase-mediated phosphorylation. Among the numerous motifs that have been implicated, an NPXXY motif (154,173) may be required for agonist-induced activation and inter-nahzation of the p -adrenergic receptor, and a dileucine motif in the carboxyl tail of many GPCRs (154) may be involved in internalization of receptors such as the Pj-adrenergic (174) and the vasopressin Via receptors (175). 

Shih, M., and Malbon, C. C. (1994) Oligodeoxynucleotides antisense to mRNA encoding protein kinase A, protein kinase C, and beta-adrenergic receptor kinase reveal distinctive cell-type-specific roles in agonist-induced desensitization. Proc. Natl. Acad. Sci. U. S. A. 91, 12193-12197. 

Eason, M. G., Moreira, S. P., and Liggett, S. B. (1995) Four consecutive serines in the third intracellular loop are the sites for beta-adrenergic receptor kinase-mediated phosphorylation and desensitization of the alpha 2A-adrenergic receptor. J. Biol. Chem. 270, 4681-4688. 

Diviani, D., Lattion, A. L., and Cotecchia, S. (1997) Characterization of the phosphorylation sites involved in G protein- coupled receptor kinase- and protein kinase C-mediated desensitization of the alphalB-adrenergic receptor. J. Biol. Chem. 272, 28712-28719. 

Bouvier, M., Hausdorff, W. P., de Blasi, A., et al. (1988) Removal of phosphorylation sites from the beta 2-adrenergic receptor delays onset of agonist-promoted desensitization. Nature. 333, 370-373. 

Seibold, A., January, B. G., Friedman, L, Hipkin, R. W., and Clark, R. B. (1998) Desensitization of beta2-adrenergic receptors with mntations of the proposed G protein-con-pled receptor kinase phosphorylation sites. J. Biol. Chem. 273, 7637-7642. 

Dawson, T. M., Arriza, J. L., Jaworsky. D. E., etal. (1993). /3-Adrenergic receptor kinase-2 and /3-arrestin-2 as mediators of odorant-induced desensitization. Science 259,825-829. 

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