RGS modulation of 5HT1A receptor signaling in depression

描述(申请人提供)：抑郁症是一种知之甚少的疾病，治疗只对一定比例的人群有效。选择性5-羟色胺再摄取抑制剂(SSRI)是最常用的抗抑郁药物。SSRI通过5-羟色胺受体间接发挥作用，包括与异源三聚体G蛋白偶联的5-HT1A受体。G蛋白信号转导调节因子(RGS)是一类细胞内蛋白家族，负向调节受体介导的G蛋白信号转导。利用突变小鼠，我们已经鉴定了5HT1A受体的一个子集，该受体与G？I2偶联，并受到RGS蛋白的负调控，这些蛋白似乎介导了SSRIs的有益行为。这使得我们认为RGS蛋白对5HT1A受体信号的调节可能在抑郁症中发挥重要作用，从而为抑郁症的治疗提供了一个新的靶点。然而，哺乳动物中有20种RGS蛋白，一种通用的抑制剂可能会产生广泛的影响。在这项建议中，我们试图确定特定的RGS蛋白，它调节5HT1A受体，从而控制与情绪障碍相关的5HT1A受体激活的行为反应。这项拟议的工作将结合行为、生化和分子生物学方法，在抑郁症动物模型中提供关于RGS蛋白质在5-羟色胺信号转导中的知识，并将RGS蛋白质作为药物靶点，以促进现有SSRI的抗抑郁作用，同时不增强它们不想要的影响。

DESCRIPTION (provided by applicant): Depression is an illness that is poorly understood and treatments are only effective in a certain percentage of the population. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant medications. SSRIs act indirectly via 5HT receptors, including the 5HT1A receptor that couples to heterotrimeric G proteins. Regulators of G protein signaling (RGS) are a family of intracellular proteins that negatively modulate receptor-mediated G protein signaling. Using mutant mice we have identified a subset of 5HT1A receptors coupled to G?i2 and negatively regulated by RGS proteins that appear to mediate the beneficial actions of SSRIs. This led us to consider that RGS protein modulation of 5HT1A receptor signaling may play an important role in depression and so present a novel target for the treatment of depression. However, there are >20 mammalian RGS proteins and a general inhibitor will likely have a broad range of effects. In this proposal we seek to identify the specific RGS protein that modulates 5HT1A receptors and therefore controls behavioral responses to 5HT1A receptor activation related to mood disorders. The proposed work will use a combination of behavioral, biochemical and molecular biological approaches to provide knowledge of RGS proteins in serotonin signaling in animal models of depression and implicate RGS proteins as drug targets to promote the antidepressant actions of currently available SSRI's without enhancing their unwanted effects.