RGS modulation of 5HT1A receptor signaling in depression

RGS 调节抑郁症中 5HT1A 受体信号

基本信息

批准号：
8452672
负责人：
John R. Traynor
金额：
$ 22.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-04 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452672
关键词：
8-Hydroxy-2-(di-n-propylamino)tetralin Acute Affect Agonist American Animal Model Animals Anti-Anxiety Agents Antidepressive Agents Anxiety Behavior Behavior Control Behavioral Biochemical Biological Brain region Chronic Control Animal Coupled Development Disease Dopamine Uptake Inhibitors Drug Targeting Drug usage Family Fluvoxamine G Protein-Coupled Receptor Genes GTP-Binding Protein Regulators GTP-Binding Proteins Heterotrimeric GTP-Binding Proteins Hippocampus (Brain)Individual Knock-out Knowledge Mediating Mental Depression Molecular Mood Disorders Moods Mus Mutant Strains Mice Norepinephrine Patients Pharmaceutical Preparations Phenotype Play Population Prefrontal Cortex Proteins RGS Proteins RNA Interference Receptor Activation Receptor Signaling Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Agents Signal Transduction Site Specificity Testing Translating Transmembrane Domain Work depressive symptoms improved inhibitor/antagonist mouse model novel novel strategies receptor receptor coupling receptor function receptor-mediated signaling response

项目摘要

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.

描述（由申请人提供）：抑郁症是一种疾病，知识较低，而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）是规定的抗抑郁药。 SSRIS通过5HT受体间接起作用，包括将伴侣与异源三聚体G蛋白偶联的5HT1A受体。 G蛋白信号传导（RGS）的调节剂是一个细胞内蛋白质的家族，负责调节受体介导的G蛋白信号传导。使用突变小鼠，我们确定了与G？i2结合的5HT1A受体的子集，并由RGS蛋白负调节，这些蛋白似乎介导了SSRI的有益作用。这使我们认为5HT1A受体信号的RGS蛋白质调节可能在抑郁症中起重要作用，因此为治疗抑郁症的新目标提供了重要的作用。但是，有20种哺乳动物的RGS蛋白，一般抑制剂可能会产生广泛的作用。在此提案中，我们试图确定调节5HT1A受体的特定RGS蛋白，因此控制对与情绪障碍有关的5HT1A受体激活的行为反应。拟议的工作将结合行为，生化和分子生物学方法的结合，以在抑郁症动物模型中提供5-羟色胺信号中RGS蛋白的知识，并将RGS蛋白作为药物靶标，以促进当前可用的SSRI的抗抑郁作用，而不增强其不受欢迎的影响。