RGS2 regulation of D2 receptor signaling

项目摘要 这个项目的总体目标是增加我们对神经生物学信号传递过程的理解 调节多巴胺的生理和行为效应。这项提案的重点是一项新的法规 RGS2(G蛋白信号转导调节因子)在中脑的D2AR信号转导 蛋白质。功能失调的中脑D2AR与神经和精神疾病有关。然而，几乎没有 关于中脑D2AR信号转导机制的知识是已知的。通过其耦合的GαI/O发送D2R信号 调节细胞和行为对刺激反应的蛋白质。Rgs蛋白家族是一个关键的负面因素 通过加速GTP水解和终止G蛋白信号来调节D2R信号。到目前为止，没有 研究检测了特定的RGS蛋白和中脑D2AR信号之间的关系 多巴胺能神经元。我们发现，苯丙胺自身给药增加了RGS2蛋白水平和 降低D2R刺激的大鼠中脑G蛋白活性。此外，RGS2和D2AR都有表达 在中脑多巴胺能神经元中。因此，RGS2和D2AR可能在功能上连锁。使用神经母细胞瘤 以N2a细胞为模型系统，我们做了一个新的观察，即RGS2负性调节D2R介导的 GαI/O信令。此外，RGS2通过其N端与D2R偶联。因此，我们假设RGS2 直接与D2R相互作用，参与独特的GαI/O信号通路，控制生理和 D2AR在中脑多巴胺能神经元的行为反应。这一假设将在两个具体的 目的：1)评估RGS2是否直接与D2R相互作用以控制D2R介导的N2a中G蛋白信号转导 以及2)确定RGS2-D2AR相互作用的生理和行为意义。 腹侧被盖区的多巴胺能神经元。这一提议有可能将《RGS2》确定为一部小说 D2R信号在体内的治疗靶点。

Project Summary The overall goal of this project is to increase our understanding of neurobiological signaling process that mediates physiological and behavioral effects of dopamine. This proposal focuses on a novel regulation of dopamine D2 autoreceptor (D2AR) signaling in the midbrain by RGS2 (regulator of G protein signaling 2) proteins. Dysfunctional midbrain D2AR is implicated in neurological and psychiatric diseases. However, little knowledge is known about the mechanisms of midbrain D2AR signaling. D2R signals via its coupled Gαi/o protein to mediate cellular and behavioral responses to stimuli. The family of RGS proteins is a key negative modulator of D2R signaling by accelerating GTP hydrolysis and terminating G protein signaling. To date, no study has examined the associations between specific RGS proteins and D2AR signaling in midbrain dopaminergic neurons. We find that amphetamine self-administration increases RGS2 protein levels and decreases D2R-stimulated G protein activation in rat midbrain. Moreover, RGS2 and D2AR are both expressed in midbrain dopaminergic neurons. Thus, RGS2 and D2AR may be functionally linked. Using neuroblastoma N2A cells as a model system, we made a novel observation that RGS2 negatively regulates D2R-mediated Gαi/o signaling. Moreover, RGS2 couples with D2R via its N-terminus. Thus, we hypothesize that RGS2 directly interacts with D2R to engage a unique Gαi/o signaling pathway that controls physiological and behavioral responses of D2AR in midbrain dopaminergic neurons. This hypothesis will be tested in two specific aims: 1) assess whether RGS2 directly interacts with D2R to control D2R-mediated G protein signaling in N2A cells; and 2) determine the physiological and behavioral significance of the RGS2-D2AR interaction in dopaminergic neurons of ventral tegmental area. This proposal has a potential to identify RGS2 as a novel therapeutic target of the D2R signaling in vivo.