Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
Neuroscience. 2010 Jan 20;165(2):535-41. doi: 10.1016/j.neuroscience.2009.10.017.
Synaptic plasticity in the striatum is a key mechanism that underlies processes such as reward related incentive learning and behavioral habit formation resulting from drugs of abuse. Key aspects of these functions are dependent on dopamine transmission as well as activation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha). In this study, we examined the ability of a recently identified heteromeric complex composed of D1 and D2 dopamine receptors coupled to Gq/11 to activate striatal CaMKIIalpha. Using the dopaminergic agonist SKF83959, which selectively activates the D1-D2 complex, we demonstrated phosphorylation of CaMKIIalpha at threonine 286, both in heterologous cells and in the murine striatum in vivo. Phosphorylation of CaMKIIalpha by activation of the receptor complex required concurrent agonism of both D1 and D2 receptors and was independent of receptor pathways that modulated adenylyl cyclase. The identification of this novel mechanism by which dopamine may modulate synaptic plasticity has implications for our understanding of striatal-mediated reward and motor function, as well as neuronal disorders in which striatal dopaminergic neurotransmission is involved.
纹状体中的突触可塑性是一种关键机制，它是奖励相关激励学习和行为习惯形成的基础，这些行为习惯的形成是由于滥用药物所致。这些功能的关键方面依赖于多巴胺传递以及钙/钙调蛋白依赖性蛋白激酶 IIα（CaMKIIα）的激活。在这项研究中，我们研究了由多巴胺 D1 和 D2 受体与 Gq/11 偶联组成的最近发现的异源二聚体复合物激活纹状体 CaMKIIα 的能力。使用多巴胺激动剂 SKF83959，它选择性地激活 D1-D2 复合物，我们证明了 CaMKIIα 在 Thr286 处的磷酸化，这既发生在异源细胞中，也发生在体内的小鼠纹状体中。受体复合物的激活导致 CaMKIIα 的磷酸化需要 D1 和 D2 受体的同时激动，并且与调节腺苷酸环化酶的受体途径无关。这种多巴胺可能调节突触可塑性的新机制的鉴定对于我们理解纹状体介导的奖励和运动功能以及涉及纹状体多巴胺能神经传递的神经元疾病具有重要意义。
