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Papers In Press, published online ahead of print February 20, 2002
Cell Physiology and Pharmacology, University of Leicester, Leicester, Leiestershire LE1 9HN
Corresponding Author: jmw23{at}le.ac.uk
We have previously shown that overexpression of G protein-coupled receptor kinase 6 (GRK6) enhanced the phosphorylation and desensitization of the endogenously expressed M 3 muscarinic acetylcholine (mACh) receptor, in human SH-SY5Y neuroblastoma cells. In this study we have examined the potential role of endogenous GRK6 in the regulation of M 3 mACh receptor by blocking its action through the introduction of a kinase-dead, dominant-negative GRK6 ( K215RGRK6). K215RGRK6 expression inhibited methacholine-stimulated M 3 mACh receptor phosphorylation by 50% compared to plasmid transfected control cells. Guanosine-5’-O-(3-[ 35S]-thio)triphosphate binding and immunoprecipitation studies, conducted after agonist pre-treatment (3 min), indicated that M 3 mACh receptor-G
J. Biol. Chem, 10.1074/jbc.M111217200
Submitted on November 26, 2001
Revised on February 20, 2002
Accepted on February 20, 2002
Endogenous GRK6 regulates M 3muscarinic acetylcholine receptor phosphorylation and desensitization in human SH-SY5Y neuroblastoma cells
q/11 uncoupling was attenuated by 50% in cells expressing K215RGRK6 when compared to control cells. In contrast, expression of the related dominant negative kinase K215RGRK5 had no effect on M 3 mACh receptor phosphorylation or uncoupling. Time-course studies also showed that agonist-stimulated [ 3H]-inositol phosphate accumulations were more sustained in cells expressing K215RGRK6, compared to control and K215RGRK5 expressing cells, while K215RGRK6 expression had no effect on the phospholipase C response to direct stimulation of G proteins with AlF 4 -. The ability of K215RGRK6 to inhibit agonist-mediated M 3 mACh receptor phosphorylation, and G protein uncoupling, suggests that endogenous GRK6 mediates, at least in part, M 3 mACh receptor desensitization in the SH-SY5Y cell line.
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