Receptors phosphorylation

Desensitization is the rapidly attenuation of receptor activation as a result of stimulation of cells and occurs in seconds to minutes. Receptor phosphorylation... 

G-protein-coupled receptor kinases (GRKs) are a family of enzymes that catalyze the phosphorylation of threonine or serine residues on G-protein-coupled receptors. Characteristically, GRKs only phosphorylate the ligand-activated form of the receptors. Phosphorylation by GRKs usually leads to impaired receptor/G-protein coupling. 

Huttenrauch F, Nitzki A, Lin FT, Honing S, Oppermann M (2002) Beta-arrestin binding to CC chemokine receptor 5 requires multiple C-terminal receptor phosphorylation sites and involves a conserved Asp-Arg-Tyr sequence motif. J Biol Chem 277 30769-30777 Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ (2004) Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor lalpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A 101 18117-18122... 

KohoutTA, Nicholas SL, Perry SJ, Reinhart G, Junger S, Struthers RS. Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J Biol Chem 2004 279(22) 23214-23222. 

Alleles encoding for altered receptor phosphorylation sites... 

Zhang L, Yunkai Y, Mackin S et al. Differential p opiate receptor phosphorylation and desensitization induced by agonists and phorbol esters. J Biol Chem 1996 271 11449-11454. 

The functioning of G proteins may be influenced by phosphorylation. G proteins, as well as their associated receptors and RGS proteins, have been reported to undergo phosphorylation by a host of protein serine/ threonine kinases and protein tyrosine kinases. While the ramifications of receptor phosphorylation are becoming increasingly well understood (see Chs 23 and 24), the effect of phosphorylation of G proteins and RGS proteins, and its role in the regulation of physiological processes, have been more difficult to establish with certainty. This remains an important area of future investigation. 

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. 

As was previously established, the spatial structure of the receptor domains is altered by interaction with the hormone, with DNA, with other proteins, and by the state of the receptor phosphorylation. Different states of folding suppose that the receptor exhibits different surfaces that permit it to gain or to lose affinity for DNA sequences or for proteins, as they are components of the native receptor or of the transcriptional machinery. The different properties that... 

Schaffhauser, H., Cai, Z., Hubalek, F., Macek, T. A., Pohl, J., Murphy, T. J., and Conn, P. J. (2000) cAMP-dependent protein kinase inhibits mGluR2 coupling to G proteins by direct receptor phosphorylation. J. Neurosci. 20, 5663-5670. 

Recently, it was shown that the thromboxane receptor itself is a substrate ofcGMP-PK and cAMP-PK in HEK293 cells, HEL cells, or with purified enzymes in vitro. Phosphorylation of its cytoplasmic carboxyterminal domain prevented the thromboxane receptor from coupling to and activating G-proteins [36, 37]. For intact platelets, TxA2 receptor phosphorylation has not yet been shown, however, it would provide another explanation for the inhibition of PLC activation and subsequent intracellular Ca2+ elevation and granule secretion in response to cyclic nucleotides. 

A paper detailing the properties of the multikinase inhibitor ABT-869 (7) did not indicate whether plasma protein binding data were used in the optimization leading to this highly protein-bound (mouse 98.2%, human 99.0%) compound [45]. A dose which provided a 69% reduction in tumor growth and >50% inhibition of receptor phosphorylation and pharmacodynamic response afforded plasma concentration that remained above the cellular IC50 for receptor phosphorylation in the presence of plasma for 4 of 12 h in the bid dosing cycle. 

Minor, L.K., Westover, L., Kong, Y., Patel, D., Wildey, M.J., Conway, B.R., and Demarest, K.T., Validation of a cell-based screen for insulin receptor modulators by quantification of insulin receptor phosphorylation, /. Biomol. Screen., 8, 439, 2003. 

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... 

Guo, J., Wu, Y., Zhang, W., Zhao, L, Devi, L. A., Pei, G., and Ma, L. (2000) Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimn-lated delta-opioid receptor phosphorylation. Mol. Pharmacol. 58, 1050-1056. 

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