Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
复制标题
DOI：
10.1523/jneurosci.5094-09.2010
复制
发表时间：
2010-04-28
期刊：
影响因子：
--
通讯作者：
Galli A
中科院分区：
文献类型：
--
作者：
Bowton E;Saunders C;Erreger K;Sakrikar D;Matthies HJ;Sen N;Jessen T;Colbran RJ;Caron MG;Javitch JA;Blakely RD;Galli A
神经递质多巴胺（DA）调节涉及注意力、奖励和运动活动的大脑回路。突触DA稳态主要通过两种突触前调节机制来控制，DA D2受体（D2R）介导的DA合成和释放的抑制，以及DA转运体（DAT）介导的DA清除。D2R可以与DAT物理结合并调节DAT功能，将DA释放和再摄取与共同机制联系起来。我们已经确定，注意力缺陷多动障碍（ADHD）相关的人类DAT编码变体Ala559Val（hDAT A559V）导致异常DA流出（ADE）类似于AMPH样精神兴奋剂引起的。在这里，我们表明D2R的紧张性激活为hDAT A559V介导的ADE提供了支持。我们确定在hDAT A559V百日咳毒素敏感，CaMKII依赖的磷酸化机制，支持D2R驱动的DA流出。这些研究确定了D2R激活下游的信号网络，通常限制突触处的DA作用，其可能被DAT突变改变以影响DA相关疾病的风险。
The neurotransmitter dopamine (DA) modulates brain circuits involved in attention, reward and motor activity. Synaptic DA homeostasis is primarily controlled via two presynaptic regulatory mechanisms, DA D2 receptor (D2R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D2Rs can physically associate with DAT and regulate DAT function, linking DA release and reuptake to a common mechanism. We have established that the attention-deficit hyperactivity disorder (ADHD)-associated human DAT coding variant Ala559Val (hDAT A559V) results in anomalous DA efflux (ADE) similar to that caused by AMPH-like psychostimulants. Here, we show that tonic activation of D2R provides support for hDAT A559V-mediated ADE. We determine in hDAT A559V a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports D2R-driven DA efflux. These studies identify a signaling network downstream of D2R activation, normally constraining DA action at synapses, that may be altered by DAT mutation to impact risk for DA related disorders.