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Molecular Pharmacology

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Research ArticleArticle

Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux

Francesca Binda, Concetta Dipace, Erica Bowton, Sabrina D. Robertson, Brandon J. Lute, Jacob U. Fog, Minjia Zhang, Namita Sen, Roger J. Colbran, Margaret E. Gnegy, Ulrik Gether, Jonathan A. Javitch, Kevin Erreger and Aurelio Galli
Molecular Pharmacology October 2008, 74 (4) 1101-1108; DOI: https://doi.org/10.1124/mol.108.048447
Francesca Binda
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Concetta Dipace
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Erica Bowton
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Sabrina D. Robertson
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Brandon J. Lute
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Jacob U. Fog
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Minjia Zhang
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Namita Sen
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Roger J. Colbran
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Margaret E. Gnegy
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Ulrik Gether
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Jonathan A. Javitch
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Kevin Erreger
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Aurelio Galli
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Abstract

The soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein syntaxin 1A (SYN1A) interacts with and regulates the function of transmembrane proteins, including ion channels and neurotransmitter transporters. Here, we define the first 33 amino acids of the N terminus of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated fraction shows that the AMPH-induced increase in DAT/SYN1A association occurs at the plasma membrane. In a superfusion assay of DA efflux, cells overexpressing SYN1A exhibited significantly greater AMPH-induced DA release with respect to control cells. By combining the patch-clamp technique with amperometry, we measured DA release under voltage clamp. At -60 mV, a physiological resting potential, AMPH did not induce DA efflux in hDAT cells and DA neurons. In contrast, perfusion of exogenous SYN1A (3 μM) into the cell with the whole-cell pipette enabled AMPH-induced DA efflux at -60 mV in both hDAT cells and DA neurons. It has been shown recently that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by AMPH and regulates AMPH-induced DA efflux. Here, we show that AMPH-induced association between DAT and SYN1A requires CaMKII activity and that inhibition of CaMKII blocks the ability of exogenous SYN1A to promote DA efflux. These data suggest that AMPH activation of CaMKII supports DAT/SYN1A association, resulting in a mode of DAT capable of DA efflux.

Footnotes

  • This work was supported by National Institutes of Health grants DA13975 (to A.G.), DA012408 (to A.G., J.A.J., and U.G.), DA022413 (to J.A.J.), DA011697 (to M.E.G.), F32-DA020306 (to K.E.), F31-MH081423 (to E.B.), F31-DA021069 (to B.J.L.), grant MH058921 (to A.G.), and by the Lundbeck Foundation (to U.G.) and the Danish Medical Research Council (U.G.).

  • F.B. and C.D. contributed equally to this work. U.G., J.A.J., K.E., and A.G. contributed equally to this work.

  • Questions related to the biophysics in this article should be addressed to K.E. (kevin.erreger{at}vanderbilt.edu).

  • ABBREVIATIONS: DA, dopamine; AMPH, amphetamine; DAT, dopamine transporter; CaMKII, Ca2+/calmodulin-dependent protein kinase II; SYN1A, syntaxin 1A; GAT, GABA transporter; SERT, serotonin transporter; NET, norepinephrine transporter; PCR, polymerase chain reaction; TBS, Tris-buffered saline; KRH, Krebs-Ringer-HEPES; HPLC, high-performance liquid chromatography; COC, cocaine; KN93, 2-(N-(2-hydroxyethyl)-N-(4-methoxybenzenesulfonyl))amino-N-(4-chlorocinnamyl)-N-methylbenzylamine.

    • Received April 30, 2008.
    • Accepted July 10, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (4)
Molecular Pharmacology
Vol. 74, Issue 4
1 Oct 2008
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Research ArticleArticle

Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux

Francesca Binda, Concetta Dipace, Erica Bowton, Sabrina D. Robertson, Brandon J. Lute, Jacob U. Fog, Minjia Zhang, Namita Sen, Roger J. Colbran, Margaret E. Gnegy, Ulrik Gether, Jonathan A. Javitch, Kevin Erreger and Aurelio Galli
Molecular Pharmacology October 1, 2008, 74 (4) 1101-1108; DOI: https://doi.org/10.1124/mol.108.048447

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Research ArticleArticle

Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux

Francesca Binda, Concetta Dipace, Erica Bowton, Sabrina D. Robertson, Brandon J. Lute, Jacob U. Fog, Minjia Zhang, Namita Sen, Roger J. Colbran, Margaret E. Gnegy, Ulrik Gether, Jonathan A. Javitch, Kevin Erreger and Aurelio Galli
Molecular Pharmacology October 1, 2008, 74 (4) 1101-1108; DOI: https://doi.org/10.1124/mol.108.048447
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