Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport.

Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, Sitte HH, Javitch JA, Galli A, Gether U
Neuron. 2006 51 (4): 417-29

PMID: 16908408 · DOI:10.1016/j.neuron.2006.06.028

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 Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a key role in this efflux. CaMKIIalpha bound to the distal C terminus of DAT and colocalized with DAT in dopaminergic neurons. CaMKIIalpha stimulated dopamine efflux via DAT in response to amphetamine in heterologous cells and in dopaminergic neurons. CaMKIIalpha phosphorylated serines in the distal N terminus of DAT in vitro, and mutation of these serines eliminated the stimulatory effects of CaMKIIalpha. A mutation of the DAT C terminus impairing CaMKIIalpha 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 CaMKIIalpha binding to the DAT C terminus facilitates phosphorylation of the DAT N terminus and mediates amphetamine-induced dopamine efflux.

MeSH Terms (28)

Amphetamines Animals Animals, Newborn Benzylamines Biological Transport Blotting, Western Calcium-Calmodulin-Dependent Protein Kinases Calcium-Calmodulin-Dependent Protein Kinase Type 2 Cells, Cultured Central Nervous System Stimulants Chromatography, High Pressure Liquid Dopamine Dopamine Plasma Membrane Transport Proteins Enzyme Inhibitors Humans Immunohistochemistry Immunoprecipitation In Vitro Techniques Membrane Potentials Mesencephalon Neurons Patch-Clamp Techniques Phosphorylation Protein Binding Protein Structure, Tertiary Rats Sulfonamides Transfection

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