Regulation of the Serotonin Transporter Function by Integrins in the Mouse Brain

小鼠大脑中整合素对血清素转运蛋白功能的调节

• 批准号: 8204549
• 负责人: ANA Marin Dias CARNEIRO
• 金额: $ 38.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-06 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204549
• 关键词: Address; Affect; Antidepressive Agents; Autistic Disorder; Behavior; Binding; Binding Sites; Biochemical; Blood; Blood Platelets; Brain; Cardiovascular Diseases; Cell Adhesion; Cell membrane; Code; Comorbidity; Complex; Coronary heart disease; Cytoskeletal Modeling; Depressive disorder; Development; Disease; Dissection; Exhibits; Fibrinogen; Functional disorder; Genetic Polymorphism; Goals; Heart Diseases; Homeostasis; Human; In Vitro; Integrin Binding; Integrin Signaling Pathway; Integrins; Knock-in Mouse; Lead; Ligand Binding; Ligands; Link; Maps; Mental disorders; Midbrain structure; Molecular; Mood Disorders; Moods; Morbidity - disease rate; Mus; Neurons; Neurotransmitters; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Physiology; Platelet aggregation; Play; Preparation; Proteins; RGD (sequence); Regulation; Risk; Risk Factors; Role; Route; Serotonin; Signal Transduction; Surface; Synapses; Synaptic plasticity; Synaptosomes; System; Techniques; Tissues; Up-Regulation; Variant; Whole Blood; adhesion receptor; base; cardiovascular disorder risk; cell type; dimer; genetic association; in vivo; information processing; insight; mortality; neuropsychiatry; novel; pointed protein; presynaptic; protein complex; public health relevance; research study; response; serotonin transporter; small molecule; trafficking; uptake

DESCRIPTION (provided by applicant): The presence of a comorbid depressive disorder increases risk for morbidity and mortality in patients with coronary heart disease. Serotonergic dysfunction is thought to contribute to mood disorders and is also a risk factor for heart disease, raising the possibility that altered 5-HT homeostasis contribute to comorbidity between neuropsychiatric and cardiovascular disorders. Recently, we discovered a physical and functional interaction between 5-HT transporter (SERT) and integrin ?3 in platelets. While integrin ?3 is essential for platelet function, SERT plays a prominent role in the modulation of neuronal 5-HT signaling. The integrin ?3 polymorphism Leu33Pro is associated with cardiovascular disease due to enhanced integrin signaling and platelet aggregation. This ?3 variant is also associated with hyperserotonemia in autistic patients, due to its upregulation of SERT surface expression and activity. Our preliminary studies indicate that integrin ?3 is expressed presynaptically (as the dimer ?V?3), where it physically associates with SERT. Additional studies suggest that manipulation of ?V?3 signaling directly influences SERT function. These findings lead to my hypothesis that the SERT/ ?V?3 complex represents a critical and conserved facet of synaptic SERT regulation, mimicking its actions in platelets. This proposal seeks 1) to elucidate the physical basis by which ?V?3 influences SERT, 2) to establish the contribution of ?V?3-based activation to SERT regulation and 3) to understand the impact of Leu33Pro ?3 coding variation on SERT function. In Aim 1, we focus on mapping the ?3 binding domain in SERT utilizing biochemical and in vitro approaches, providing a route to the development of small peptides that can disrupt SERT/ ?V?3 interactions ex vivo. In Aim 2, we utilize small molecule ?V?3 ligands to delineate the influence of ?V?3 activation on SERT function ex vivo, as well as 5-HT clearance in vivo. In Aim 3, we determine the effects of the Leu33Pro ?3 variant on 5-HT levels and SERT activity in both platelets and in the brain. We hypothesize that the expression of integrin Pro33?3 will lead to constitutively- elevated SERT function in platelets and brain. Together, these studies represent the first opportunity to examine the presynaptic impact of ?V?3 and help elucidate pathways supporting comorbidity between mental illness and cardiovascular disease. PUBLIC HEALTH RELEVANCE: The proposed project aims to understand how integrins modulate the serotonin system using molecular and biochemical approaches. As mood disorders are associated with impaired information processing, the association between a cell adhesion receptor and the major target for antidepressant therapy reveals a novel mechanism affected by mood disorders. The protein complex studied in detail in this proposal is also a common molecular feature of mood and cardiovascular disease and provides clues to understanding the comorbidities between the two disorders.

描述（由申请人提供）：合并抑郁症的存在会增加冠心病患者的发病和死亡风险。 5-羟色胺功能障碍被认为会导致情绪障碍，也是心脏病的危险因素，这增加了 5-HT 稳态改变导致神经精神疾病和心血管疾病之间共病的可能性。最近，我们发现血小板中 5-HT 转运蛋白 (SERT) 和整合素 α3 之间存在物理和功能相互作用。虽然整合素 α3 对于血小板功能至关重要，但 SERT 在神经元 5-HT 信号传导的调节中发挥着重要作用。由于整合素信号传导和血小板聚集增强，整合素β3 多态性 Leu33Pro 与心血管疾病相关。这种 ?3 变异还与自闭症患者的高血清素血症相关，因为它上调了 SERT 表面表达和活性。我们的初步研究表明，整合素α3 在突触前表达（作为二聚体αVβ3），它与SERT 有物理联系。其他研究表明，操纵 ?V?3 信号传导直接影响 SERT 功能。这些发现引出了我的假设：SERT/?V?3 复合体代表了突触 SERT 调节的一个关键且保守的方面，模仿了其在血小板中的作用。该提案旨在 1) 阐明 ?V?3 影响 SERT 的物理基础，2) 确定基于 ?V?3 的激活对 SERT 调节的贡献，以及 3) 了解 Leu33Pro ?3 编码变异对 SERT 功能的影响。在目标 1 中，我们重点利用生化和体外方法绘制 SERT 中的 α3 结合域，为开发可破坏 SERT/αVβ3 离体相互作用的小肽提供了一条途径。在目标 2 中，我们利用小分子 ?V?3 配体来描述 ?V?3 激活对离体 SERT 功能以及体内 5-HT 清除的影响。在目标 3 中，我们确定了 Leu33Pro ?3 变体对血小板和大脑中 5-HT 水平和 SERT 活性的影响。我们假设整合素 Pro33?3 的表达将导致血小板和大脑中 SERT 功能的组成性升高。总之，这些研究首次有机会检查 ?V?3 的突触前影响，并帮助阐明支持精神疾病和心血管疾病之间共病的途径。 公共健康相关性：拟议项目旨在了解整合素如何使用分子和生化方法调节血清素系统。由于情绪障碍与信息处理受损有关，细胞粘附受体与抗抑郁治疗的主要靶点之间的关联揭示了一种受情绪障碍影响的新机制。该提案中详细研究的蛋白质复合物也是情绪和心血管疾病的常见分子特征，并为理解这两种疾病之间的共病提供了线索。