Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport
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Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. / Fog, Jacob U; Khoshbouei, Habibeh; Holy, Marion; Owens, William A; Vaegter, Christian Bjerggaard; Sen, Namita; Nikandrova, Yelyzaveta; Bowton, Erica; McMahon, Douglas G; Colbran, Roger J; Daws, Lynette C; Sitte, Harald H; Javitch, Jonathan A; Galli, Aurelio; Gether, Ulrik.
In: Neuron, Vol. 51, No. 4, 2006, p. 417-429.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport
AU - Fog, Jacob U
AU - Khoshbouei, Habibeh
AU - Holy, Marion
AU - Owens, William A
AU - Vaegter, Christian Bjerggaard
AU - Sen, Namita
AU - Nikandrova, Yelyzaveta
AU - Bowton, Erica
AU - McMahon, Douglas G
AU - Colbran, Roger J
AU - Daws, Lynette C
AU - Sitte, Harald H
AU - Javitch, Jonathan A
AU - Galli, Aurelio
AU - Gether, Ulrik
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
KW - Amphetamines
KW - Animals
KW - Animals, Newborn
KW - Benzylamines
KW - Biological Transport
KW - Blotting, Western
KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2
KW - Calcium-Calmodulin-Dependent Protein Kinases
KW - Cells, Cultured
KW - Central Nervous System Stimulants
KW - Chromatography, High Pressure Liquid
KW - Dopamine
KW - Dopamine Plasma Membrane Transport Proteins
KW - Enzyme Inhibitors
KW - Humans
KW - Immunohistochemistry
KW - Immunoprecipitation
KW - Membrane Potentials
KW - Mesencephalon
KW - Neurons
KW - Patch-Clamp Techniques
KW - Phosphorylation
KW - Protein Binding
KW - Protein Structure, Tertiary
KW - Rats
KW - Sulfonamides
KW - Transfection
U2 - 10.1016/j.neuron.2006.06.028
DO - 10.1016/j.neuron.2006.06.028
M3 - Journal article
C2 - 16908408
VL - 51
SP - 417
EP - 429
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 4
ER -
ID: 1200628