Regulators of G-protein signaling 4:: modulation of 5-HT1A-mediated neurotransmitter release in vivo
Regulators of G-protein signaling 4:: modulation of 5-HT1A-mediated neurotransmitter release in vivo
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DOI：
10.1016/j.brainres.2004.06.073
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发表时间：
2004-10-01
期刊：
影响因子：
2.9
通讯作者：
Young, KH
中科院分区：
文献类型：
--
作者：
Beyer, CE;Ghavami, A;Young, KH
G蛋白信号调节因子(RGS)在G蛋白偶联受体(GPCRs)的信号转导中起着关键作用。具体地说，RGS蛋白作为GTP酶加速蛋白(GAP)发挥作用，以抑制或“负面调节”GPCR介导的信号。我们的团队最近发现，RGS4有效地阻断了表达5-HT1A受体的CHO细胞中Galpha(I)介导的信号转导。然而，体内是否存在类似的关系还有待确定。用复制缺陷型单纯疱疹病毒(HSV)上调大鼠中缝背核(DRN)RGS4基因的表达，同时用体内微透析法监测纹状体细胞外5-羟色胺(5-HT)的水平。在未感染的大鼠身上进行的初步实验表明，急性给予8-OH-DPAT(0.01-0.3 mg/kg，皮下[S.C.])剂量依赖性地降低纹状体5-羟色胺的水平，这种效应被认为是由于激活DRN中的躯体树突状细胞5-HT1A自身受体所致。对照组大鼠DRN内单次注射HSV-LacZ，8-OH-DPAT(0.03 mg/kg，S.C.)降低5-羟色胺水平的程度与在未感染动物中观察到的程度相似。相反，在DRN感染HSV-RGS4的大鼠对8-OH-DPAT(0.03 mg/kg，s.c.)表现出迟钝的神经化学反应；然而，将剂量增加到0.3 mg/kg则逆转了这一效应。总之，这些发现代表了第一个体内证据表明RGS4具有GAP Galpha(I)偶联受体的功能，并表明针对RGS蛋白的药物发现努力可能代表了一种新的机制来操纵5-HT1A介导的神经递质释放。(C)2004爱思唯尔B.V.保留所有权利。
Regulators of G-protein signaling (RGS) play a key role in the signal transduction of G-protein-coupled receptors (GPCRs). Specifically, RGS proteins function as GTPase accelerating proteins (GAPs) to dampen or "negatively regulate" GPCR-mediated signaling. Our group recently showed that RGS4 effectively GAPs Galpha(i)-mediated signaling in CHO cells expressing the serotonin-1A (5-HT1A) receptor. However, whether a similar relationship exists in vivo has yet to be identified. In present studies, a replication-deficient herpes simplex virus (HSV) was used to elevate RGS4 mRNA in the rat dorsal raphe nuclei (DRN) while extracellular levels of 5-HT in the striatum were monitored by in vivo microdialysis. Initial experiments conducted with noninfected rats showed that acute administration of 8-OH-DPAT (0.01-0.3 mg/kg, subcutaneous [s.c.]) dose dependently decreased striatal levels of 5-HT, an effect postulated to result from activation of somatodendritic 5-HT1A autoreceptors in the DRN. In control rats receiving a single intra-DRN infusion of HSV-LacZ, 8-OH-DPAT (0.03 mg/kg, s.c.) decreased 5-HT levels to an extent similar to that observed in noninfected animals. Conversely, rats infected with HSV-RGS4 in the DRN showed a blunted neurochemical response to 8-OH-DPAT (0.03 mg/kg, s.c.); however, increasing the dose to 0.3 mg/kg reversed this effect. Together, these findings represent the first in vivo evidence demonstrating that RGS4 functions to GAP Galpha(i)-coupled receptors and suggest that drug discovery efforts targeting RGS proteins may represent a novel mechanism to manipulate 5-HT1A-mediated neurotransmitter release. (C) 2004 Elsevier B.V. All rights reserved.