Gq-Coupled Receptors Inhibit PI 3-kinase/Akt Signaling

描述(由申请人提供)：本提案的目的是 了解通过Gaq蛋白传递信号的受体是如何 调节磷脂酰肌醇(PI)3-激酶及其下游效应蛋白Akt。 需要评估的假设是GQ偶联受体的激活 抑制生长因子对PI3K/Akt信号转导的刺激 路径。PI3K和Akt的激活在胰岛素中起重要作用 葡萄糖代谢的调节。PI3-激酶和Akt的抑制作用 解释为什么许多荷尔蒙通过GQ偶联受体来对抗 胰岛素作用的影响。由于胰岛素抵抗是糖尿病的一个显著特征 II型糖尿病，发现GQ-Couble使用的机制 受体抑制这一信号通路将增加我们对 糖尿病。具体目的是确定GQ偶联受体是否抑制 生长因子与胰岛素激活PI3-激酶的关系及其机制探讨 这种抑制作用的机制。此外，它的抑制作用 将在体内检测GQ偶联受体对胰岛素的作用，以期 更好地了解胰岛素抵抗的病理生理学。具体目标1 将在三种不同的细胞类型中使用GQ偶联受体来评估 假设的概括性。原始性活性的腺病毒表达 Gaq将指示Gaq是否足以抑制PI3-激酶和Akt。一个 Gaq/11-将使用空单元线来确定此操作是否需要Gaq 抑制效应。具体目标2将集中在确定酪氨酸是否 受体酪氨酸激酶或其底物的去磷酸化是一种 Gaq抑制PI3-激酶激活的机制。具体目标3 将首先确定对大鼠A1肾上腺素能受体的急性刺激 含药物激动剂的肝脏阻断PI3-激酶的胰岛素激活 信号通路。SPICAL AIM 3还将调查胰岛素抵抗 果糖喂养大鼠肝脏中A1肾上腺素能的慢性激活 受体导致PI3-激酶/Akt信号的抑制。成功 完成这项建议可能会导致更好的理解和治疗 治疗人类糖尿病的药物。

DESCRIPTION (provided by applicant): The objective of this proposal is to understand how receptors that transmit their signals through the Gaq protein regulate phosphatidylinositol (PI) 3-kinase and its downstream effector Akt. The hypothesis to be evaluated is that activation of Gq-coupled receptors inhibits growth factor stimulation of the PI 3-kinase/Akt signal transduction pathway. Activation of PI 3-kinase and Akt plays an important role in insulin regulation of glucose metabolism. Inhibition of PI 3-kinase and Akt might explain why many hormones that act through Gq-coupled receptors counter the effect of insulin action. Since insulin resistance is a prominent feature in type II diabetes mellitus, discovering the mechanisms used by Gq-coupled receptors to inhibit this signaling pathway will increase our understanding of diabetes. The specific aims are to determine if Gq-coupled receptors inhibit growth factor and insulin activation of PI 3-kinase and to explore the mechanisms of this inhibitory effect. In addition, the inhibitory effect of Gq-coupled receptors on insulin action will be examined in vivo in order to better understand the pathophysiology of insulin resistance. Specific Aim 1 will use Gq-coupled receptors in three diverse cell types to assess the generality of the hypothesis. Adenoviral expression of constitutively active Gaq will indicate if Gaq is sufficient to inhibit PI 3-kinase and Akt. A Gaq/11-null cell line will be used to determine if Gaq is necessary for this inhibitory effect. Specific Aim 2 will focus on determining whether tyrosine dephosphorylation of receptor tyrosine kinases or their substrates is a mechanism utilized by Gaq to inhibit PI 3-kinase activation. Specific Aim 3 will first determine if acute stimulation of a1 adrenergic receptors in rat liver with a pharmacologic agonist blocks insulin activation of the PI 3-kinase signaling pathway. Specific Aim 3 will also investigate if insulin resistance in the liver of fructose-fed rats is due to chronic activation of a1 adrenergic receptors that leads to inhibition of PI 3-kinase/Akt signaling. Successful completion of this proposal may lead to a better understanding of and treatment for diabetes mellitus in humans.