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J. Biol. Chem., Vol. 280, Issue 12, 10914-10919, March 25, 2005

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Regulation of Amphetamine-stimulated Dopamine Efflux by Protein Kinase C ^*

L'Aurelle A. Johnson, Bipasha Guptaroy, David Lund, Susanna Shamban, and Margaret E. Gnegy

From the Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632

Evidence suggests that protein kinase C (PKC) and intracellular calcium are important for amphetamine-stimulated outward transport of dopamine in rat striatum. In this study, we examined the effect of select PKC isoforms on amphetamine-stimulated dopamine efflux, focusing on Ca²⁺-dependent forms of PKC. Efflux of endogenous dopamine was measured in superfused rat striatal slices; dopamine was measured by high performance liquid chromatography. The non-selective classical PKC inhibitor Gö6976 inhibited amphetamine-stimulated dopamine efflux, whereas rottlerin, a specific inhibitor of PKC, had no effect. A highly specific PKC inhibitor, LY379196, blocked dopamine efflux that was stimulated by either amphetamine or the PKC activator, 12-O-tetradecanoylphorbol-13-acetate. None of the PKC inhibitors significantly altered [³H]dopamine uptake. PKC_I and PKC_II, but not PKC or PKC, were co-immunoprecipitated from rat striatal membranes with the dopamine transporter (DAT). Conversely, antisera to PKC_I and PKC_II but not PKC or PKC were able to co-immunoprecipitate DAT. Amphetamine-stimulated dopamine efflux was significantly enhanced in hDAT-HEK 293 cells transfected with PKC_II as compared with hDAT-HEK 293 cells alone, or hDAT-HEK 293 cells transfected with PKC or PKC_I. These results suggest that classical PKC_II is physically associated with DAT and is important in maintaining the amphetamine-stimulated outward transport of dopamine in rat striatum.

Received for publication, December 9, 2004 , and in revised form, January 11, 2005.

^* This work was supported by National Institutes of Health Grant DA11697, Pharmacological Sciences Training Grant GM07767, and Michigan Diabetes Research and Training Center Grant 5P60DK-20572 from the NIDDK, 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.

To whom correspondence should be addressed: Dept. of Pharmacology, 2220E MSRB III, University of Michigan Medical School, Ann Arbor, MI 48109-0632. Tel.: 734-763-5358; Fax: 734-763-4450; E-mail: pgnegy{at}umich.edu.

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