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，治疗方法只对一定比例的人群有效。选择性血清素再摄取抑制剂（SSRIs）是最常用的抗抑郁药物。SSRIs通过5HT受体间接作用，包括与异源三聚体G蛋白偶联的5HT1A受体。G蛋白信号调节因子（regulatory of G protein signaling， RGS）是一个细胞内蛋白家族，可负调控受体介导的G蛋白信号。使用突变小鼠，我们已经确定了5HT1A受体与G？i2并受RGS蛋白负调控，RGS蛋白似乎介导了SSRIs的有益作用。这使我们考虑到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，因此为抑郁症的治疗提供了新的靶点。然而，哺乳动物的RGS蛋白有大约20种，一种普通的抑制剂可能会有广泛的作用。在本提案中，我们试图确定调节5HT1A受体的特定RGS蛋白，从而控制与情绪障碍相关的5HT1A受体激活的行为反应。这项工作将结合行为学、生物化学和分子生物学的方法，提供抑郁症动物模型中血清素信号传导中的RGS蛋白的知识，并暗示RGS蛋白作为药物靶点，以促进当前可用的SSRI的抗抑郁作用，而不会增强其不良影响。

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.