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

J. Biol. Chem., Vol. 282, Issue 49, 35842-35854, December 7, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/49/35842    most recent M611758200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Zapata, A. Articles by Shippenberg, T. S. Search for Related Content PubMed PubMed Citation Articles by Zapata, A. Articles by Shippenberg, T. S. Social Bookmarking                      What's this?

Regulation of Dopamine Transporter Function and Cell Surface Expression by D3 Dopamine Receptors^*

Agustin Zapata¹, Bronwyn Kivell¹, Yang Han, Jonathan A. Javitch, Elizabeth A. Bolan, David Kuraguntla, Vanaja Jaligam, Murat Oz, Lankupalle D. Jayanthi^¶, Devadoss J. Samuvel^¶, Sammanda Ramamoorthy^¶2, and Toni S. Shippenberg²³

From the Integrative Neuroscience Section, National Institutes of Health/National Institute on Drug Abuse Intramural Research Program/Department of Health and Human Services, Baltimore, Maryland 21224, the Departments of Psychiatry and Pharmacology, Center for Molecular Recognition, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and the ^¶Department of Neurosciences, Division of Neuroscience Research, Medical University of South Carolina, Charleston, South Carolina 29425

D₃ dopamine receptors are expressed by dopamine neurons and are implicated in the modulation of presynaptic dopamine neurotransmission. The mechanisms underlying this modulation remain ill defined. The dopamine transporter, which terminates dopamine transmission via reuptake of released neurotransmitter, is regulated by receptor- and second messenger-linked signaling pathways. Whether D3 receptors regulate dopamine transporter function is unknown. We addressed this issue using a fluorescent imaging technique that permits real time quantification of dopamine transporter function in living single cells. Accumulation of the fluorescent dopamine transporter substrate trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium (ASP⁺) in human embryonic kidney cells expressing human dopamine transporter was saturable and temperature-dependent. In cells co-expressing dopamine transporter and D3 receptors, the D2/D3 agonist quinpirole produced a rapid, concentration-dependent, and pertussis toxin-sensitive increase of ASP⁺ uptake. Similar agonist effects were observed in Neuro2A cells and replicated in human embryonic kidney cells using a radioligand uptake assay in which binding to and activation of D3 receptors by [³H]dopamine was prevented. D3 receptor stimulation activated phosphoinositide 3-kinase and MAPK. Inhibition of either kinase prevented the quinpirole-induced increase in uptake. D3 receptor activation differentially affected dopamine transporter function and subcellular distribution depending on the duration of agonist exposure. Biotinylation experiments revealed that the rapid increase of uptake was associated with increased cell surface and decreased intracellular expression and increased dopamine transporter exocytosis. In contrast, prolonged agonist exposure reduced uptake and transporter cell surface expression. These results demonstrate that D3 receptors regulate dopamine transporter function and identify a novel mechanism by which D3 receptors regulate extracellular dopamine concentrations.

Received for publication, December 22, 2006 , and in revised form, September 28, 2007.

^* This work was supported by the National Institutes of Health/National Institute on Drug Abuse (NIDA) Intramural Research Program and National Institute on Drug Abuse and National Institutes of Health Grants P50DA015369, MH062612 (to S. R.), GM081054 (to L. D. J.), MH57324, MH54137, and DA11495 (to J. A. J.). 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 Both authors contributed equally and should be considered first authors.

² Both authors contributed equally and should be considered senior authors.

³ To whom correspondence should be addressed: Integrative Neuroscience Section, NIDA, 5500 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-550-1514; E-mail: tshippen{at}intra.nida.nih.gov.

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

This article has been cited by other articles:

				R. Chen, C. A. Furman, M. Zhang, M. N. Kim, R. W. Gereau IV, M. Leitges, and M. E. Gnegy Protein Kinase C{beta} Is a Critical Regulator of Dopamine Transporter Trafficking and Regulates the Behavioral Response to Amphetamine in Mice J. Pharmacol. Exp. Ther., March 1, 2009; 328(3): 912 - 920. [Abstract] [Full Text] [PDF]

				J. M. Witkin, B. Levant, A. Zapata, R. Kaminski, and M. Gasior The Dopamine D3/D2 Agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] Protects against Acute and Cocaine-Kindled Seizures in Mice: Further Evidence for the Involvement of D3 Receptors J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 930 - 938. [Abstract] [Full Text] [PDF]

				D. J. Samuvel, L. D. Jayanthi, S. Manohar, K. Kaliyaperumal, R. E. See, and S. Ramamoorthy Dysregulation of Dopamine Transporter Trafficking and Function after Abstinence from Cocaine Self-Administration in Rats: Evidence for Differential Regulation in Caudate Putamen and Nucleus Accumbens J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 293 - 301. [Abstract] [Full Text] [PDF]