Beaulieu Jean-Martin, Gainetdinov Raul R, Caron Marc G
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Trends Pharmacol Sci. 2007 Apr;28(4):166-72. doi: 10.1016/j.tips.2007.02.006. Epub 2007 Mar 8.
Drugs that act on dopamine neurotransmission are important tools for the management of multiple neuropsychiatric disorders. Classically, dopamine receptors have been shown to regulate cAMP-PKA (protein kinase A) and Ca(2+) pathways through G-protein-mediated signaling. However, it has become apparent that, in addition to this canonical action, D(2)-class dopamine receptors can function through a protein kinase B (Akt)-GSK-3 (glycogen synthase kinase 3) signaling cascade. This novel signaling mode involves the multifunctional scaffolding protein beta-arrestin 2, which has a role in G-protein-coupled receptor (GPCR) desensitization. In this article, we provide an overview of how this dual function of components of the GPCR desensitization machinery relates to dopamine-receptor-mediated responses and we summarize recent insights into the relevance of the Akt-GSK-3 signaling cascade for the expression of dopamine-associated behaviors and the actions of dopaminergic drugs.
作用于多巴胺神经传递的药物是治疗多种神经精神疾病的重要工具。传统上，多巴胺受体已被证明可通过G蛋白介导的信号传导调节cAMP-PKA（蛋白激酶A）和Ca(2+)途径。然而，显而易见的是，除了这种经典作用外，D(2)类多巴胺受体还可通过蛋白激酶B（Akt）-糖原合酶激酶3（GSK-3）信号级联发挥作用。这种新的信号传导模式涉及多功能支架蛋白β-抑制蛋白2，其在G蛋白偶联受体（GPCR）脱敏中起作用。在本文中，我们概述了GPCR脱敏机制成分的这种双重功能与多巴胺受体介导的反应之间的关系，并总结了关于Akt-GSK-3信号级联与多巴胺相关行为表达及多巴胺能药物作用相关性的最新见解。
