Ca(2+)/calmodulin-dependent protein kinase IIα (αCaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome.
The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signaling. DAT is also the primary target of psychostimulant drugs such as cocaine and amphetamines. Conversely, methylphenidate and amphetamine are both used clinically in the treatment of attention-deficit hyperactivity disorder and narcolepsy. The action of amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase αCaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP(+)) efflux. More importantly, αCaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that αCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack αCaMKII or which express a permanently self-inhibited αCaMKII (αCaMKII(T305D)), exhibit significantly reduced amphetamine-triggered DAT-mediated MPP(+) efflux. Additionally, we investigated mice that mimic a neurogenetic disease known as Angelman syndrome. These mice possess reduced αCaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the αCaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
Thomas
T
Steinkellner
Jae-Won
JW
Yang
Therese R
TR
Montgomery
Wei-Qiang
WQ
Chen
Marie-Therese
MT
Winkler
Sonja
S
Sucic
Gert
G
Lubec
Michael
M
Freissmuth
Ype
Y
Elgersma
Harald H
HH
Sitte
Oliver
O
Kudlacek
D019943:Amino Acid Substitution; D000661:Amphetamine / Q000494:pharmacology; D017204:Angelman Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D000661:Amphetamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse