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J. Biol. Chem., Vol. 280, Issue 49, 40442-40449, December 9, 2005

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Psychoactive Substrates Stimulate Dopamine Transporter Phosphorylation and Down-regulation by Cocaine-sensitive and Protein Kinase C-dependent Mechanisms^*

From the Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202

Dopamine transporters (DATs) undergo intracellular sequestration and functional down-regulation upon exposure to psychostimulant substrates. To investigate the potential mechanism underlying these responses, we examined the acute in vitro and in vivo effects of amphetamine and methamphetamine (METH) on phosphorylation and down-regulation of rat DAT using wild type and N-terminal truncation mutants. Phosphorylation of DAT assessed by ³²PO₄ metabolic labeling was increased up to 2-fold by in vitro treatment of rDAT LLC-PK₁ cells with amphetamine or METH and was similarly increased in rat striatal tissue by in vitro application or in vivo injection of METH. The dopamine transport blocker (-)-cocaine did not affect DAT phosphorylation but prevented the phosphorylation increase induced by METH. Phosphorylation of DAT induced by METH was also prevented by the protein kinase C blocker bisindoylmaleimide I and was absent in an N-terminally truncated protein that lacks the first 21 residues including 6 serines that also represent the site of phorbol ester induced phosphorylation. Down-regulation of transport induced by METH was also cocaine- and protein kinase C-dependent but was retained in the N-terminal truncation mutant. These results demonstrate that transport or binding of METH stimulates DAT phosphorylation and down-regulation by a mechanism that requires protein kinase C but that METH-induced down-regulation can occur independently of direct transporter phosphorylation. The finding that DAT phosphorylation is stimulated by amphetamines reveals a previously unknown effect of these drugs that is not produced by cocaine and may be related to reinforcement.

Received for publication, February 22, 2005 , and in revised form, September 30, 2005.

^* This work was supported by Grants F31 DA17520 (to M. A. C.) and RO1 DA13147 (to R. A. V.) from the National Institute on Drug Abuse and Grant ND EPSCoR IIG (to R. A. V. and J. D. F.). 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.

¹ To whom correspondence should be addressed. Tel.: 701-777-3419; Fax: 701-777-2382; E-mail: rvaughan{at}medicine.nodak.edu.

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