@article{e2f276cafb1942d79eaee08225b8a3dc,
title = "Calmodulin Kinase II Interacts with the Dopamine Transporter C Terminus to Regulate Amphetamine-Induced Reverse Transport",
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.",
keywords = "CELLBIO, SIGNALING",
author = "Fog, {Jacob U.} and Habibeh Khoshbouei and Marion Holy and Owens, {William A.} and Vaegter, {Christian Bjerggaard} and Namita Sen and Yelyzaveta Nikandrova and Erica Bowton and McMahon, {Douglas G.} and Colbran, {Roger J.} and Daws, {Lynette C.} and Sitte, {Harald H.} and Javitch, {Jonathan A.} and Aurelio Galli and Ulrik Gether",
note = "Funding Information: We thank Lisbeth Andersen and Martha Bass for technical assistance and Dr. Jan Egebjerg and Kenneth L. Madsen for helpful comments. We thank Dr. David Sulzer for helpful comments and help setting up postnatal cultures of midbrain neurons. J.U.F. was the recipient of a fellowship supported by the Medicon Valley Academy and H. Lundbeck A/S. The work was supported in part by the National Institute of Health Grants P01 DA 12408 (U.G., A.G., and J.A.J.), DA 11495 (J.A.J.), MH 57324 (J.A.J), DA 13975 (A.G.), DA 14684 (A.G), DA 18992 (L.C.D), MH 63232 (R.J.C.), and EY 15815 (D.G.M.), the Danish Research Councils, the Lundbeck Foundation (U.G.), the Novo Nordic Foundation (U.G.), the A.P Moeller Foundation (U.G.), and grant P17076-B02 by the Austrian Science Foundation/FWF (H.H.S). ",
year = "2006",
month = aug,
day = "17",
doi = "10.1016/j.neuron.2006.06.028",
language = "English (US)",
volume = "51",
pages = "417--429",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}