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J. Biol. Chem., Vol. 279, Issue 10, 8779-8786, March 5, 2004

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Regulation of the Neuronal Nicotinic Acetylcholine Receptor by Src Family Tyrosine Kinases^*

Kan Wang, John T. Hackett, Michael E. Cox, Monique van Hoek¶, Jon M. Lindstrom||, and Sarah J. Parsons**

From the Department of Microbiology and Cancer Center and the Department of Physiology, University of Virginia, Charlottesville, Virginia 22908, the ^||Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the ^¶Center for Biodefense, George Mason University, Manassas, Virginia 20110

Src family kinases (SFKs) are abundant in chromaffin cells that reside in the adrenal medulla and respond to cholinergic stimulation by secreting catecholamines. Our previous work indicated that SFKs regulate acetylcholine- or nicotine-induced secretion, but the site of modulatory action was unclear. Using whole cell recordings, we found that inhibition of SFK tyrosine kinase activity by PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine) treatment or expression of a kinase-defective c-Src reduced the peak amplitude of nicotine-induced currents in chromaffin cells or in human embryonic kidney cells ectopically expressing functional neuronal 345 acetylcholine receptors (AChRs). Conversely, the phosphotyrosine phosphatase inhibitor, sodium vanadate, or expression of mutationally activated c-Src resulted in enhanced current amplitudes. These results suggest that SFKs and putative phosphotyrosine phosphatases regulate the activity of AChRs by opposing actions. This proposed model was supported further by the findings that SFKs physically associate with the receptor and that the AChR is tyrosine-phosphorylated.

Received for publication, September 2, 2003 , and in revised form, November 24, 2003.

^* This work was supported by Grant P01 CA40042 from the NCI, National Institutes of Health. 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.

Present address: Dept. of Surgery, University of British Columbia, Vancouver, B. C. V6H 3Z6, Canada.

^** To whom correspondence should be addressed: Dept. of Microbiology, University of Virginia Health System, P. O. Box 800734, Charlottesville, VA 22908. Tel.: 804-924-2352; Fax: 804-982-0689; E-mail: sap{at}virginia.edu.

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