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Research ArticleArticle

Amphetamine Induces a Calcium/Calmodulin-Dependent Protein Kinase II-Dependent Reduction in Norepinephrine Transporter Surface Expression Linked to Changes in Syntaxin 1A/Transporter Complexes

Concetta Dipace, Uhna Sung, Francesca Binda, Randy D. Blakely and Aurelio Galli
Molecular Pharmacology January 2007, 71 (1) 230-239; DOI: https://doi.org/10.1124/mol.106.026690
Concetta Dipace
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Uhna Sung
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Francesca Binda
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Randy D. Blakely
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Aurelio Galli
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Abstract

Norepinephrine (NE) transporters (NETs) are high-affinity transport proteins that mediate the synaptic clearance of NE after vesicular release. NETs represent a major therapeutic target for antidepressants and are targets of multiple psychostimulants including amphetamine (AMPH) and cocaine. Recently, we demonstrated that syntaxin 1A (SYN1A) regulates NET surface expression and, through binding to the transporter's NH2 terminus, regulates transporter catalytic function. AMPH induces NE efflux and may also regulate transporter trafficking. We monitored NET distribution and function in catecholaminergic cell lines (CAD) stably transfected with either full-length human NET (CAD-hNET) or with an hNET N-terminal deletion (CAD-hNETΔ28-47 cells). In hNET-CAD cells, AMPH causes a slow and small reduction of surface hNET with a modest increase in hNET/SYN1A associations at the plasma membrane. In contrast, in CAD-hNETΔ28-47 cells, AMPH induces a rapid and substantial reduction in surface hNETΔ28-47 accompanied by a large increase in plasma membrane hNETΔ28-47/SYN1A complexes. We also found that AMPH in CAD-hNETΔ28-47 cells induces a robust increase in cytosolic Ca2+ and concomitant activation of calcium/calmodulin-dependent protein kinase II (CaMKII). Inhibition of either the increase in intracellular Ca2+ or CaMKII activity blocks AMPH-stimulated hNETΔ28-47 trafficking and the formation of hNETΔ28-47/SYN1A complexes. Here, we demonstrate that AMPH stimulation of CAMKII stabilizes an hNET/SYN1A complex. This hNET/SYN1A complex rapidly redistributes, upon AMPH treatment, when mechanisms supported by the transporter's NH2 terminus are eliminated.

Footnotes

  • This work was supported by National Institutes of Health grants MH058921 and DA14684 (to A.G).

  • R.D.B. and A.G. contributed equally to this work.

  • ABBREVIATIONS: NET, norepinephrine transporter; AMPH, amphetamine; NE, norepinephrine; CaMKII, calcium/calmodulin-dependent protein kinase II; SYN1A, syntaxin 1A; CAD, catecholaminergic cell line; h, human; PKC, protein kinase C; DAT, dopamine transporter; HA, hemagglutinin; His, histidine; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester; PBS, phosphate-buffered saline; PMSF, phenylmethylsulfonyl fluoride; PAGE, polyacrylamide gel electrophoresis; CTR, vehicle; DMI, desipramine; IP, immunoprecipitate; ANOVA, analysis of variance; KN-93, 2-(N-(2-hydroxyethyl)-N-(4-methoxybenzenesulfonyl))amino-N-(4-chlorocinnamyl)-N-methylbenzylamine; KN-92, 2-[N-(4′-methoxybenzenesulfonyl)]amino-N-(4′-chlorophenyl)-2-propenil-N-methylbenzylamine.

    • Received May 15, 2006.
    • Accepted October 6, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (1)
Molecular Pharmacology
Vol. 71, Issue 1
1 Jan 2007
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Research ArticleArticle

Amphetamine Induces a Calcium/Calmodulin-Dependent Protein Kinase II-Dependent Reduction in Norepinephrine Transporter Surface Expression Linked to Changes in Syntaxin 1A/Transporter Complexes

Concetta Dipace, Uhna Sung, Francesca Binda, Randy D. Blakely and Aurelio Galli
Molecular Pharmacology January 1, 2007, 71 (1) 230-239; DOI: https://doi.org/10.1124/mol.106.026690

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Research ArticleArticle

Amphetamine Induces a Calcium/Calmodulin-Dependent Protein Kinase II-Dependent Reduction in Norepinephrine Transporter Surface Expression Linked to Changes in Syntaxin 1A/Transporter Complexes

Concetta Dipace, Uhna Sung, Francesca Binda, Randy D. Blakely and Aurelio Galli
Molecular Pharmacology January 1, 2007, 71 (1) 230-239; DOI: https://doi.org/10.1124/mol.106.026690
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