REGULATION OF HYPOTHALAMIC SIGNALING BY RGS4 PROTEIN

描述（申请人摘要）：本提案将审查 调节G蛋白信号传导（RGS）蛋白在调节G蛋白 在体内连接的信号转导。RGS蛋白是一类新的蛋白质家族 增加与G-α亚基结合的GTP的水解， 激活第二信使系统。因此，RGS水平的变化 蛋白质可以介导G蛋白的反应性的增加或减少。 蛋白偶联受体我们已经证明，一种基因的过度表达 特定的RGS蛋白，RGS 4，可以诱导脱敏的一个成员， 培养细胞中的5-HT 2受体家族。然而，目前尚不清楚是否 RGS 4蛋白在体内对哺乳动物脑中的5-HT 2受体具有相同的作用。 反义寡核苷酸策略将被用来检验这一假设 RGS 4蛋白调节下丘脑中的5-HT 2A受体信号。我们 将测试下丘脑中5-HT 2A受体适应的调节 室旁核，因为它含有丰富的RGS 4蛋白水平 和5-HT 2A受体，该核中的5-HT 2A受体可以被脱敏或 对几种治疗变得超级敏感，因为激素对 激动剂治疗可用作受体信号传导的灵敏量度， 下丘脑我们将使用反义寡核苷酸策略来减少 RGS 4蛋白的水平1）引起信号传导的超敏感性和2） 减轻慢性应激诱导的5-HT 2A信号转导的脱敏作用 用5-HT 2A/2C激动剂DOI治疗。最后，我们的初步数据表明， RGS 4蛋白表达在氟西汀诱导的5-HT 2A 受体超敏性我们的研究已经排除了几种可能 机制，并导致了一种假设，即RGS 4水平的降低 蛋白质可以调节这种超敏感性。因此，我们将研究 RGS 4蛋白减少的时间过程与 表达和氟西汀诱导的5-HT 2A受体超敏性。的 拟议研究的结果将提供新的见解， RGS蛋白在体内的表达，以及5-HT 2A受体系统的调节机制。 鉴于G蛋白信号在哺乳动物大脑中的重要性， 来了解RGS蛋白的调节。由于其突出的作用 5-HT 2A受体在神经精神疾病的病因学中起作用， 了解RGS对5-HT 2A信号传导适应性变化的调节 蛋白质将为治疗干预的新靶点奠定基础 治疗这些疾病

DESCRIPTION (Applicant's abstract): This proposal will examine the role that regulatory G protein signaling (RGS) proteins play in modulating G-protein linked signal transduction in vivo. RGS proteins are a novel family of proteins that increase the hydrolysis of GTP bound to the G-alpha subunit and reduce the activation of the second messenger system. Thus, changes in the levels of RGS proteins may mediate increases or decreases in the responsiveness of G protein-coupled receptors. We have demonstrated that overexpression of one particular RGS protein, RGS4, can induce desensitization of one member of the 5-HT2 receptor family in cells in culture. However, it is not known whether RGS4 protein has the same effect on 5-HT2 receptors in mammalian brain in vivo. Antisense oligodeoxynucleotide strategies will be used to test the hypothesis that RGS4 protein regulates 5-HT2A receptor signaling in the hypothalamus. We will test the regulation of 5-HT2A receptor adaptation in the hypothalamic paraventricular nucleus, because it contains abundant levels of RGS4 protein and 5-HT2A receptors, 5-HT2A receptors in this nucleus can be desensitized or become supersensitive with several treatments, and because hormone responses to agonist treatment can be used as a sensitive measure of receptor signaling in the hypothalamus. We will use antisense oligonucleotide strategies to reduce the levels of RGS4 protein to 1) cause supersensitivity of signaling and 2) attenuate the desensitization of 5-HT2A signal transduction, induced by chronic treatment with the 5-HT2A/2C agonist DOI. Lastly, our preliminary data suggest that RGS4 protein expression is decreased during fluoxetine-induced 5-HT2A receptor supersensitivity. Our studies have ruled out several possible mechanisms and have led to the hypothesis that a decrease in the levels of RGS4 proteins could mediate this supersensitivity. Thus, we will examine the correspondence between the time course of the reduction in RGS4 protein expression and of fluoxetine-induced 5-HT2A receptor supersensitivity. The results of the proposed studies will provide new insight into the function of RGS proteins in vivo, and the mechanisms regulating 5-HT2A receptor systems. Given the importance of G protein signaling in mammalian brain, it is essential to understand the regulation of RGS proteins. Because of the prominent role that 5-HT2A receptors play in the etiology of neuropsychiatric disorders, understanding the regulation of adaptive changes in 5-HT2A signaling by RGS proteins will lay the foundation for new targets for therapeutic intervention for these disorders.