Ca2+/Calmodulin-dependent Protein Kinase II alpha (alpha CaMKII) 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 alpha CaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP+) efflux. More importantly, alpha 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 alpha CaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack alpha CaMKII or which express a permanently self-inhibited alpha CaMKII (alpha CaMKIIT305D), 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 alpha CaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the alpha CaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.