G protein signaling in the C. elegans nervous system

线虫神经系统中的 G 蛋白信号传导

• 批准号: 8213463
• 负责人: MICHAEL R KOELLE
• 金额: $ 55.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-08 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213463
• 关键词: Affect; Animal Model; Animals; Autoreceptors; Back; Behavior; Binding; Biochemical; Biological Models; Brain; Caenorhabditis elegans; Cells; Chemicals; Complex; Coupled; Defect; Event; Feedback; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gated Ion Channel; Genes; Genetic; Genetic Screening; Goals; Guanine Nucleotide Exchange Factors; Health; Heterotrimeric GTP-Binding Proteins; Human; Intervention; Ion Channel; Knock-out; Light; Locomotion; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Modeling; Molecular; Motor Neurons; Movement; Muscle; Muscle Contraction; Mutation; Nervous system structure; Neurons; Neurotransmitters; Nucleotides; Physiological; Potassium Channel; Proteins; Receptor Activation; Receptor Signaling; Role; Scaffolding Protein; Schizophrenia; Second Messenger Systems; Serotonin; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Synapses; Tertiary Protein Structure; Testing; Work; design; effective therapy; egg; genetic analysis; in vitro testing; in vivo; insight; mutant; novel; postsynaptic; receptor; receptor coupling; receptor function; response; second messenger; serotonin receptor

DESCRIPTION (provided by applicant): We seek to understand how neurotransmitters signal through heterotrimeric G proteins to modulate the activities of neurons. We will focus on the mechanism of signaling by serotonin, defects in which are thought to underlie major depression in humans. Our goal is to understand how the many G protein coupled serotonin receptors function together to mediate appropriate responses to this neurotransmitter, and to find out what happens downstream of receptor activation. C. elegans uses serotonin as a neurotransmitter, and we will use this model system to investigate the mechanism of three different serotonin signaling events. In our first aim, we will characterize a signaling complex that mediates serotonin signaling onto the C. elegans egg-laying muscles. We will test a model in which multiple serotonin receptors and an ERG potassium channel are co-localized to postsynaptic structures so that localized signals produced by serotonin receptor signaling can inhibit the ERG channel to promote muscle contraction. In the second aim, we will study the mechanism by which serotonin released onto the egg-laying muscles also signals back onto the neurons that release it via autoreceptors to feedback inhibit further serotonin release. We will use a combination of genetic and biochemical studies to analyze two new types of signaling regulators that our preliminary results show enhance such feedback signaling: a GPR/GoLoco protein which binds G1 subunits, and the RIC-8 protein which acts as a G protein nucleotide exchange factor. In the third aim, we will study the mechanism by which serotonin signals to slow down C. elegans locomotion behavior. We have used a genetic screen to identify genes required for this serotonin signaling event. We found that two different serotonin receptors are each required for the effect of serotonin on locomotion: knocking out either receptor alone or both together leads to the same strong defect in serotonin response. We will study how these two different serotonin receptors work together. We will also comprehensively analyze a new protein identified by our screen that is required specifically for serotonin signaling, but that is not similar to any protein previously known to be involved in serotonin signaling. The mechanisms of serotonin signaling are highly conserved between C. elegans and humans and the insights made possible by the power of the C. elegans model system should shed light on new details of human serotonin signaling. This will ultimately help to understand the causes of depression and the interventions that can be used to treat it. PUBLIC HEALTH RELEVANCE: This proposal investigates the basic mechanisms by which neurons in the brain communicate with each other using chemical neurotransmitters, focusing in particular on the neurotransmitter serotonin. Defects in signaling by serotonin and other neurotransmitters appear to underlie depression, schizophrenia and other disorders of mental health, but the precise details of these defects are in most cases unknown. Understanding in detail how neurotransmitters act should make it possible to precisely define the defects that cause mental disorders and to thus develop effective treatments for them.)

描述（由申请人提供）：我们试图了解神经递质如何通过异源三聚体G蛋白发出信号以调节神经元的活动。我们将集中在5-羟色胺的信号机制，其中的缺陷被认为是人类重度抑郁症的基础。我们的目标是了解许多G蛋白偶联的5-羟色胺受体如何共同发挥作用，以介导对这种神经递质的适当反应，并找出受体激活的下游发生了什么。C. elegans使用血清素作为神经递质，我们将使用这个模型系统来研究三种不同的血清素信号事件的机制。 在我们的第一个目标，我们将描述一个信号复合物，介导血清素信号到C。线虫产卵的肌肉。我们将测试一种模型，其中多种5-羟色胺受体和ERG钾通道共定位于突触后结构，使得由5-羟色胺受体信号传导产生的局部信号可以抑制ERG通道以促进肌肉收缩。 在第二个目标中，我们将研究释放到产卵肌肉上的5-羟色胺也通过自身受体向神经元发出信号的机制，以反馈抑制进一步的5-羟色胺释放。我们将使用遗传学和生物化学研究的组合来分析两种新类型的信号调节剂，我们的初步结果表明，它们增强了这种反馈信号：结合G1亚基的GPR/GoLoco蛋白，以及作为G蛋白核苷酸交换因子的RIC-8蛋白。 在第三个目标中，我们将研究5-羟色胺信号减缓C的机制。elegans运动行为我们已经使用了遗传筛选来识别这种血清素信号事件所需的基因。我们发现，两种不同的5-羟色胺受体都是5-羟色胺对运动产生影响所必需的：单独或同时敲除其中一种受体都会导致5-羟色胺反应的强烈缺陷。我们将研究这两种不同的血清素受体如何协同工作。我们还将全面分析通过我们的筛选鉴定的一种新蛋白质，该蛋白质是血清素信号传导特异性所需的，但与先前已知的参与血清素信号传导的任何蛋白质都不相似。 5-羟色胺信号传导机制在C.线虫和人类以及C. elegans模型系统应该揭示人类血清素信号的新细节。这最终将有助于了解抑郁症的原因以及可用于治疗抑郁症的干预措施。 公共卫生关系：该提案研究了大脑中神经元使用化学神经递质相互通信的基本机制，特别关注神经递质血清素。5-羟色胺和其他神经递质的信号缺陷似乎是抑郁症、精神分裂症和其他精神健康疾病的基础，但在大多数情况下，这些缺陷的确切细节是未知的。详细了解神经递质的作用方式，应该可以精确定义导致精神障碍的缺陷，从而开发出有效的治疗方法。）