Orphan Receptors in Regulation of Neuronal G Protein Signaling

神经元 G 蛋白信号传导调节中的孤儿受体

• 批准号: 10358596
• 负责人: Kirill A. Martemyanov
• 金额: $ 64.02万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-06 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358596
• 关键词: Ablation; Address; Affect; Affective; Alleles; Animal Model; Antidepressive Agents; Anxiety; Attention; Autopsy; Behavior; Behavioral; Binding; Biochemical; Biochemistry; Biological; Biology; Brain; Brain Diseases; Cell Adhesion; Cell membrane; Cells; Cellular Assay; Complex; Consensus; Corpus striatum structure; Cyclic AMP; Data; Development; Diagnosis; Disease; Dissection; Electrophysiology (science); Elements; Event; Extracellular Matrix; FDA approved; Family; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Proteins; Generations; Glucocorticoids; Goals; Grant; Heparan Sulfate Proteoglycan; Hormones; Human; Ion Channel; Knockout Mice; Label; Lead; Ligands; Major Depressive Disorder; Mammals; Mediating; Mediator of activation protein; Memory; Mental Depression; Molecular; Moods; Mus; Nervous System Physiology; Nervous system structure; Neurologic; Neurons; Neurotransmitter Receptor; Neurotransmitters; Orphan; Osteocalcin; Pathologic; Pathway interactions; Patients; Peptides; Perception; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Play; Population; Potassium Channel; Process; Production; Proteins; Proteolytic Processing; Proteomics; Reaction; Regulation; Reporter; Reporting; Research; Role; Second Messenger Systems; Sensory; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Stress; Synaptic Transmission; Technology; Testing; Therapeutic; Therapeutic Intervention; base; design; drug development; extracellular; frontier; genetic manipulation; innovation; insight; interest; member; mood regulation; neuronal circuitry; neuronal excitability; neuropsychiatry; neuroregulation; neurotransmission; novel; novel strategies; optical sensor; overexpression; receptor; recruit; stress resilience; success; therapeutic development; therapeutic target; trafficking; trait; treatment strategy

PROJECT SUMMARY G protein coupled receptor (GPCR) signaling pathways mediate actions of hormones and neurotransmitters. They are essential for normal function of the nervous system, frequently disrupted in many neuropsychiatric and neurological conditions and/or exploited for therapeutic purposes. While we learned considerable information about molecular players involved in traditional GPCR signaling, many critical gaps remain. Among biggest uncharted territories in the field is an issue of “orphan” GPCRs, receptors with unknown signaling mechanisms. It is generally recognized that orphan receptors have tremendous potential for uncovering novel biology of the nervous system and harnessing it for potential therapeutic benefits. Our long- term goal is to understand principles in organization and functional regulation of poorly explored GPCR pathways in the effort to develop better treatments for brain disorders. The focus of our attention is on poorly understood orphan receptor- GPR158, yet one of the most abundant GPCRs in the brain. We found that GPR158 plays a pivotal role in stress-induced depression. Its expression is induced by glucocorticoids and is upregulated in patients with major depressive disorder. Conversely, GPR158 elimination in mice produces marked anti-depressant phenotype and stress resilience. At the molecular level, GPR158 recruits negative regulator of G protein signaling, RGS7 to the plasma membrane impacting production of the second messenger cAMP to control synaptic transmission and neuronal excitability. The proposal is focused on filling two biggest gaps in our understanding of GPR158 biology: its activation mechanisms and identity of effectors mediating its effects on neuronal circuitry underlying affective states. Intriguingly, our Preliminary Data revealed network of GPR158 extracellular interactions with the cell- adhesion like proteins and pointed to a cAMP-modulated K+ channel complex as a possible signaling mediator. Based on accumulated preliminary data we hypothesize that GPR158 transduces signals triggered by extracellular binding partners into changes of neuronal excitability by engaging inhibitory ion channel complex. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to: (1) determine molecular mechanisms by which GPR158 transduces its signals, (2) dissect circuits that rely on GPR158 action to exert behavioral effects and (3) probe the involvement of the K+ channel complex in mediating the effect of GPR158 on neuronal excitability. The strategy proposed to address these Aims will entail a synergistic combination of biochemical, electrophysiological and cell-biological approaches, exploiting the existence of a powerful array of technologies and animal models. We hope that accomplishment of these goals will provide critical new insights into the mood regulation in mammals and suggest novel targets for the development of therapeutic interventions.

项目概要 G 蛋白偶联受体 (GPCR) 信号通路介导激素和激素的作用 神经递质。它们对于神经系统的正常功能至关重要，但在许多情况下经常受到干扰 神经精神和神经系统疾病和/或用于治疗目的。当我们学习的时候 关于参与传统 GPCR 信号转导的分子参与者的大量信息，许多关键差距 保持。该领域最大的未知领域之一是“孤儿”GPCR 问题，即具有 未知的信号传导机制。人们普遍认为孤儿受体具有巨大的潜力 揭示神经系统的新生物学并利用它获得潜在的治疗益处。我们的长期 术语目标是了解尚未探索的 GPCR 的组织原理和功能调节 努力开发更好的脑部疾病治疗方法。 我们关注的焦点是人们知之甚少的孤儿受体 - GPR158，但它是最重要的孤儿受体之一。 大脑中存在丰富的 GPCR。我们发现 GPR158 在压力诱发的抑郁症中发挥着关键作用。它是 该表达由糖皮质激素诱导，并在患有重度抑郁症的患者中上调。 相反，消除小鼠中的 GPR158 会产生显着的抗抑郁表型和应激恢复能力。在 在分子水平上，GPR158 将 G 蛋白信号传导的负调节因子 RGS7 招募到质膜 影响第二信使 cAMP 的产生，以控制突触传递和神经元兴奋性。 该提案的重点是填补我们对 GPR158 生物学理解的两个最大空白：其激活 调节其对情感状态下的神经元回路的影响的效应器的机制和身份。 有趣的是，我们的初步数据揭示了 GPR158 细胞外与细胞相互作用的网络- 粘附蛋白，并指出 cAMP 调节的 K+ 通道复合物作为可能的信号传导介质。 根据积累的初步数据，我们假设 GPR158 转导由以下因素触发的信号： 通过接合抑制性离子通道复合物，细胞外结合伙伴改变神经元兴奋性。 该假设将通过追求三个互补的具体目标来检验，这些目标旨在：（1）确定 GPR158 转导信号的分子机制，(2) 剖析依赖 GPR158 的电路 (3) 探究 K+ 通道复合物在介导 GPR158 对神经元兴奋性的影响。为实现这些目标而提出的战略将需要协同作用 结合生物化学、电生理学和细胞生物学方法，利用 一系列强大的技术和动物模型。我们希望这些目标的实现将提供 对哺乳动物情绪调节的重要新见解，并提出了发展的新目标 治疗干预。