Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, 71003 Crete, Greece.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8254-9. doi: 10.1073/pnas.1214696110. Epub 2013 Apr 29.
Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.
G 蛋白信号调节蛋白 4（Rgs4）是一种信号转导蛋白，通过与 Gα 亚基相互作用，控制单胺、阿片类、毒蕈碱和其他 G 蛋白偶联受体的功能。Rgs4 在参与情绪、运动、认知和成瘾的几个脑区表达，并受精神药物、应激和皮质类固醇的调节。在这项研究中，我们使用遗传小鼠模型和病毒介导的基因转移来研究 Rgs4 在抗抑郁药物作用中的作用。我们首先分析了人类死后的脑组织，发现接受靶向单胺系统的标准抗抑郁药物治疗的患者的伏隔核（NAc）中 RGS4 表达有明显上调。缺乏 Rgs4 的小鼠的行为研究，包括 NAc 中的特定敲低，表明该脑区中的 Rgs4 作为几种单胺靶向抗抑郁药物（包括三环类抗抑郁药、选择性 5-羟色胺再摄取抑制剂和去甲肾上腺素再摄取抑制剂）的抗抑郁样和抗痛觉过敏样作用的正调节剂。使用 NAc 中病毒介导的 Rgs4 活性增加的研究进一步支持了这一假设。有趣的是，在前额叶皮层中，Rgs4 作为非单胺靶向药物（被认为是抗抑郁药）作用的负调节剂：N-甲基-D-天冬氨酸谷氨酸受体拮抗剂氯胺酮和 δ 阿片受体激动剂 (+)-4-[(αR)-α-((2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基]-N,N-二乙基苯甲酰胺。总之，这些数据揭示了 Rgs4 在广泛的抗抑郁药物的脑区特异性作用中的独特调节作用，并表明在 RGS4 活性水平的药理学干预可能增强用于治疗抑郁和神经病理性疼痛的此类药物的作用。
