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Ca(2+)/calmodulin-dependent protein kinase II? (?CaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome.

ABSTRACT: 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 ?CaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP(+)) efflux. More importantly, ?CaMKII 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 ?CaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack ?CaMKII or which express a permanently self-inhibited ?CaMKII (?CaMKII(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 ?CaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the ?CaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.

SUBMITTER: Steinkellner T

PROVIDER: S-EPMC3436163 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Ca(2+)/calmodulin-dependent protein kinase IIα (αCaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome.

Steinkellner Thomas T Yang Jae-Won JW Montgomery Therese R TR Chen Wei-Qiang WQ Winkler Marie-Therese MT Sucic Sonja S Lubec Gert G Freissmuth Michael M Elgersma Ype Y Sitte Harald H HH Kudlacek Oliver O

The Journal of biological chemistry 20120709 35

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 int ...[more]

PMID: 22778257

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Dataset Information

Ca(2+)/calmodulin-dependent protein kinase II? (?CaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome.

Publications

Ca(2+)/calmodulin-dependent protein kinase IIα (αCaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome.

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