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

描述（由申请人提供）：冠心病患者合并抑郁障碍的存在增加了发病率和死亡率的风险。5-羟色胺能功能障碍被认为有助于情绪障碍，也是心脏病的危险因素，提高了改变5-HT稳态有助于神经精神疾病和心血管疾病之间的共病的可能性。最近，我们发现5-HT转运体（SERT）和整合素之间的物理和功能的相互作用？3血小板。而整合素？3是血小板功能所必需的，SERT在神经元5-HT信号转导的调节中起着突出的作用。整合素？3多态性Leu 33 Pro与心血管疾病相关，这是由于整合素信号传导和血小板聚集增强。这个吗？3变体也与自闭症患者的高胆固醇血症相关，这是由于其上调SERT表面表达和活性。我们的初步研究表明，整合素？3是表达突触前（作为二聚体？V？3），在那里它与SERT物理关联。其他研究表明，操纵？小维3信号直接影响SERT功能。这些发现导致我的假设，SERT/？小维3复合物代表突触SERT调节的关键和保守方面，模仿其在血小板中的作用。这一建议旨在：1）阐明物理基础？小维3影响SERT，2）建立的贡献？小维3-基于激活SERT调节和3）了解Leu 33 Pro的影响？3 SERT函数的编码变化。在目标1中，我们专注于映射？3结合结构域的SERT利用生物化学和体外方法，提供了一种途径的小肽，可以破坏SERT/？小维3种离体相互作用。在目标2中，我们利用小分子？小维3配体描绘的影响？小维3对SERT功能的体外激活，以及体内5-HT清除。在目的3中，我们确定的Leu 33 Pro？3变体对血小板和脑中5-HT水平和SERT活性的影响。我们推测，整合素Pro33？3将导致血小板和脑中SERT功能的组成性升高。总之，这些研究代表了第一次有机会检查突触前的影响？V？3并有助于阐明支持精神疾病和心血管疾病之间共病的途径。

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.