Calmodulin Kinase II Interacts with the Dopamine Transporter C Terminus to Regulate Amphetamine-Induced Reverse Transport

Jacob U. Fog, Habibeh Khoshbouei, Marion Holy, William A. Owens, Christian Bjerggaard Vaegter, Namita Sen, Yelyzaveta Nikandrova, Erica Bowton, Douglas G. McMahon, Roger J. Colbran, Lynette C. Daws, Harald H. Sitte, Jonathan A. Javitch, Aurelio Galli, Ulrik Gether

Research output: Contribution to journalArticle

161 Scopus citations

Abstract

Efflux of dopamine through the dopamine transporter (DAT) is critical for the psychostimulatory properties of amphetamines, but the underlying mechanism is unclear. Here we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a key role in this efflux. CaMKIIα bound to the distal C terminus of DAT and colocalized with DAT in dopaminergic neurons. CaMKIIα stimulated dopamine efflux via DAT in response to amphetamine in heterologous cells and in dopaminergic neurons. CaMKIIα phosphorylated serines in the distal N terminus of DAT in vitro, and mutation of these serines eliminated the stimulatory effects of CaMKIIα. A mutation of the DAT C terminus impairing CaMKIIα binding also impaired amphetamine-induced dopamine efflux. An in vivo role for CaMKII was supported by chronoamperometry measurements showing reduced amphetamine-induced dopamine efflux in response to the CaMKII inhibitor KN93. Our data suggest that CaMKIIα binding to the DAT C terminus facilitates phosphorylation of the DAT N terminus and mediates amphetamine-induced dopamine efflux.

Original languageEnglish (US)
Pages (from-to)417-429
Number of pages13
JournalNeuron
Volume51
Issue number4
DOIs
StatePublished - Aug 17 2006

Keywords

  • CELLBIO
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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    Fog, J. U., Khoshbouei, H., Holy, M., Owens, W. A., Vaegter, C. B., Sen, N., Nikandrova, Y., Bowton, E., McMahon, D. G., Colbran, R. J., Daws, L. C., Sitte, H. H., Javitch, J. A., Galli, A., & Gether, U. (2006). Calmodulin Kinase II Interacts with the Dopamine Transporter C Terminus to Regulate Amphetamine-Induced Reverse Transport. Neuron, 51(4), 417-429. https://doi.org/10.1016/j.neuron.2006.06.028