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 多巴胺D2受体(D2R)通过RGS2(G蛋白信号转导调节因子2)蛋白在中脑进行信号转导。 中脑功能障碍的D2R与神经和精神疾病有关。然而，几乎没有人知道 已经知道了中脑D2R信号的机制。这项提议将勾勒出机械的 RGS2在多巴胺能神经元D2R信号转导中的作用 中脑D2R介导的多巴胺生理和行为。 D2R信号通过其偶联的GαI/O蛋白来介导细胞和行为对刺激的反应。他的家人 RGS蛋白是D2R信号的关键负调制子，通过加速GTP水解和终止G 蛋白质信号。到目前为止，还没有研究检查特定的RGS蛋白和D2R之间的联系 中脑多巴胺能神经元的信号传导。我们发现安非他明自我给药会增加RGS2 并降低D2R刺激的大鼠中脑G蛋白活性。此外，RGS2和 躯体树突状D2R在中脑多巴胺能神经元中均有表达。因此，RGS2和D2R可能是 在神经系统中从未被研究过的功能相连的。用神经母细胞瘤N2A细胞作为 模型系统中，我们发现RGS2负性调节D2R介导的G-αI/O信号。 此外，RGS2通过其N端与D2R偶联。因此，我们假设RGS2直接与 D2R参与控制D2R生理和行为反应的独特GαI/O信号通路 在中脑多巴胺能神经元中。这一假设将在两个具体目标中得到检验：1)评估 RGS2直接与D2R相互作用，控制D2R在神经元样细胞系中介导的G蛋白信号； 确定多巴胺能神经元中RGS2-D2R相互作用的生理和行为意义 腹侧被盖区。这项建议可能会扩大D2R监管的曲目和多样性，并具有 在体内鉴定RGS2为D2R信号网络新成分的可能性

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 receptor (D2R) signaling in the midbrain by RGS2 (regulator of G protein signaling 2) protein. Dysfunctional midbrain D2R is implicated in neurological and psychiatric diseases. However, little knowledge is known about the mechanisms of midbrain D2R signaling. This proposal will delineate the mechanistic actions of RGS2 on D2R signaling and interrogate RGS2 in dopaminergic neurons as a critical modulator of midbrain D2R-mediated dopamine physiology and behavior. 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 D2R 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 somatodendritic D2R are both expressed in midbrain dopaminergic neurons. Thus, RGS2 and D2R may be functionally linked which has never been examined in a neuronal system. Using neuroblastoma N2A cells as a model system, we made the 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 D2R 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 neuron-like cell lines; and 2) determine the physiological and behavioral significance of the RGS2-D2R interaction in dopaminergic neurons of ventral tegmental area. This proposal may expand the repertoire and diversity of D2R regulation and has a potential to identify RGS2 as a novel component of the D2R signaling network in vivo