| First Author | Steinkellner T | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 35 | Pages | 29627-35 |
| PubMed ID | 22778257 | Mgi Jnum | J:190420 |
| Mgi Id | MGI:5448811 | Doi | 10.1074/jbc.M112.367219 |
| Citation | Steinkellner T, et al. (2012) Ca(2+)/calmodulin-dependent protein kinase IIalpha (alphaCaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome. J Biol Chem 287(35):29627-35 |
| abstractText | 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 alphaCaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP(+)) efflux. More importantly, alphaCaMKII 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 alphaCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack alphaCaMKII or which express a permanently self-inhibited alphaCaMKII (alphaCaMKII(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 alphaCaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the alphaCaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome. |
