HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 50, 52059-52068, December 10, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/50/52059    most recent M407085200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dobransky, T. Articles by Rylett, R. J. Search for Related Content PubMed PubMed Citation Articles by Dobransky, T. Articles by Rylett, R. J. Social Bookmarking                      What's this?

Protein Kinase C Isoforms Differentially Phosphorylate Human Choline Acetyltransferase Regulating Its Catalytic Activity^*

Tomas Dobransky, Amanda Doherty-Kirby¶, Ae-Ri Kim¶, Dyanne Brewer¶||, Gilles Lajoie¶, and Rebecca J. Rylett**

From the Departments of Physiology and Pharmacology and ^¶Biochemistry, University of Western Ontario and Cell Biology Research Group, and Robarts Research Institute, London, Ontario N6A 5C1, Canada

Choline acetyltransferase (ChAT) synthesizes acetylcholine in cholinergic neurons; regulation of its activity or response to physiological stimuli is poorly understood. We show that ChAT is differentially phosphorylated by protein kinase C (PKC) isoforms on four serines (Ser-440, Ser-346, Ser-347, and Ser-476) and one threonine (Thr-255). This phosphorylation is hierarchical, with phosphorylation at Ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. Ser-476 with Ser-440 and Ser-346/347 maintains basal ChAT activity. Ser-440 is targeted by Arg-442 for phosphorylation by PKC. Arg-442 is mutated spontaneously (R442H) in congenital myasthenic syndrome, rendering ChAT inactive and causing neuromuscular failure. This mutation eliminates phosphorylation of Ser-440, and Arg-442, not phosphorylation of Ser-440, appears primarily responsible for ChAT activity, with Ser-440 phosphorylation modulating catalysis. Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity.

Received for publication, June 24, 2004 , and in revised form, September 16, 2004.

^* This work was supported by an operating grant from the Canadian Institutes for Health Research (to R. J. R.), and NSERC and ORDCF (to G. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Current address: Dept. of Molecular Biology & Genetics, University of Guelph, Guelph, Ontario N1G 2W1, Canada.

^** To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada. Tel.: 519-663-5777; Fax: 519-663-3314; E-mail: jane.rylett{at}fmd.uwo.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?