RGS modulation of 5HT1A receptor signaling in depression

描述（由申请人提供）：抑郁症是一种人们知之甚少的疾病，治疗仅在一定比例的人群中有效。选择性5-羟色胺再摄取抑制剂（SSRIs）是最常用的抗抑郁药物。SSRIs通过5 HT受体间接起作用，包括与异源三聚体G蛋白偶联的5 HT 1A受体。G蛋白信号调节因子（Regulators of G protein signaling，RGS）是一类负性调节受体介导的G蛋白信号转导的细胞内蛋白。使用突变小鼠，我们已经确定了一个子集的5 HT 1A受体耦合到G？i2和负调控的RGS蛋白，似乎介导SSRIs的有益作用。这使我们认为RGS蛋白对5 HT 1A受体信号的调节可能在抑郁症中起重要作用，因此为抑郁症的治疗提供了一个新的靶点。然而，存在>20种哺乳动物RGS蛋白，并且一般抑制剂将可能具有广泛的影响。在本提案中，我们试图识别调节5 HT 1A受体的特定RGS蛋白，从而控制与情绪障碍相关的5 HT 1A受体激活的行为反应。拟议的工作将使用行为，生物化学和分子生物学方法的组合，以提供RGS蛋白在抑郁症动物模型中的5-羟色胺信号传导的知识，并暗示RGS蛋白作为药物靶点，以促进目前可用的SSRI的抗抑郁作用，而不会增强其不必要的作用。

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.