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J. Biol. Chem., Vol. 275, Issue 26, 19667-19675, June 30, 2000
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From the Department of Cell Physiology and Pharmacology, University
of Leicester, P. O. Box 138, Medical Sciences Building,
University Road, Leicester LE1 9HN, United Kingdom
Agonist-mediated receptor phosphorylation by one
or more of the members of the G-protein receptor kinase (GRK) family is
an established model for G-protein-coupled receptor (GPCR)
phosphorylation resulting in receptor desensitization. Our recent
studies have, however, suggested that an alternative route to GPCR
phosphorylation may be an operation involving casein kinase 1
Phosphorylation and Regulation of a Gq/11-coupled
Receptor by Casein Kinase 1
*
(CK1). In the current study we investigate the involvement of CK1
in the phosphorylation of the human m3-muscarinic receptor in intact
cells. We show that expression of a catalytically inactive mutant of
CK1, designed to act in a dominant negative manner, inhibits
agonist-mediated receptor phosphorylation by ~40% in COS-7 and
HEK-293 cells. Furthermore, we present evidence that a peptide
corresponding to the third intracellular loop of the m3-muscarinic
receptor (Ser345-Leu463) is an inhibitor
of CK1 due to its ability to both act as a pseudo-substrate for
CK1 and form a high affinity complex with CK1. Expression of this
peptide was able to reduce both basal and agonist-mediated
m3-muscarinic receptor phosphorylation in intact cells. These results
support the notion that CK1 is able to mediate GPCR phosphorylation
in an agonist-dependent manner and that this may provide a
novel mechanism for GPCR phosphorylation. The functional role of
phosphorylation was investigated using a mutant of the m3-muscarinic
receptor that showed an ~80% reduction in agonist-mediated
phosphorylation. Surprisingly, this mutant underwent agonist-mediated
desensitization suggesting that, unlike many GPCRs, desensitization of
the m3-muscarinic receptor is not mediated by receptor phosphorylation.
The inositol (1,4,5)-trisphosphate response did, however, appear to be
dramatically potentiated in the phosphorylation-deficient mutant
indicating that phosphorylation may instead control the magnitude of
the initial inositol phosphate response.
*
This work was supported by the Wellcome Trust Grant
047600/Z/96.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 0116-2522935;
Fax: 0116-252 5045; E-mail: TBA@le.ac.uk.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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