STRUCTURE/FUNCTION OF ALPHA-1 ADRENERGIC RECEPTORS

由G蛋白偶联受体激活引起的信号具有 变得越来越复杂。现在已知这些受体 与酪氨酸激酶和细胞因子受体相关的途径， 尽管所涉及的机制尚不清楚。肾上腺素能受体 (ARs)影响许多细胞的生长和分化，通常通过 丝裂原活化蛋白（MAP）激酶途径的激活。我们有 显示α/1A-AR转染的PC 12细胞，去甲肾上腺素激活 三个平行的MAP激酶途径，并导致分化为一个 与神经生长因子引起的神经元表型相似。 初步数据表明，这些反应不涉及已知的 第二信使，我们现在建议使用这些细胞来检查 由α/1-AR激活引发的复杂信号传导事件。我们将 测试假设，α/1-AR激活信号通路， 除了Gq/11介导的Ca/2+动员和蛋白激酶C 这些反应可能涉及或可能不涉及异源三聚体G 蛋白质，它们可能是不同的三个α-1AR 亚型：我们将确定1）人类α/1a-，α/1B和 α/1D-AR差异激活第二信使、MAP激酶和 PC 12细胞中的转录反应; 2）是否已知第二 信使途径和/或G蛋白参与MAPK应答; 3） α/1- AR亚型是否激活Jak/Stat或其他生长因子 因子/细胞因子信号传导途径;和4）使用α/1-AR激活 MAPK的三个途径，以阐明其在生长中的作用， 分化和凋亡。这些实验将阐明 将AR活化与生长和分化偶联，并提供 关于密切相关亚型之间差异的重要信息。

The signals elicited by activation of G protein coupled receptors have become increasingly complex. These receptors are now known to activate pathways associated with tyrosine kinase and cytokine receptors, although the mechanisms involved are not yet clear. Adrenergic receptors (ARs) affect growth and differentiation of many cells, often through activation of mitogen-activated protein (MAP) kinase pathways. We have shown that alpha/1A-AR transfected PC12 cells, norepinephrine activates three parallel MAP kinase pathways and causes differentiation into a neuronal phenotype similar to that caused by nerve growth factor. Preliminary data suggests that these responses do not involve known second messengers, and we now propose to use these cells to examine the complex signaling events initiated by alpha/1-AR activation. We will test the hypothesis that alpha/1-ARs activate signaling pathways in addition to Gq/11-mediated Ca/2+ mobilization and protein kinase C activation, that these responses may or may not involve heterotrimeric G proteins, and that they may be different for the three alpha-1AR subtypes: We will determine 1) whether human alpha/1a-, and alpha/1B and alpha/1D-ARs differentially activate second messenger, MAP kinase, and transcriptional responses in PC12 cells; 2) whether known second messenger pathways and/or G proteins are involved in MAPK responses; 3) whether alpha/1- AR subtypes activate Jak/Stat or other growth factor/cytokine signaling pathways; and 4) use alpha/1-AR activation of the three MAPK pathways to clarify their roles in growth, differentiation and apoptosis. These experiments will clarify mechanisms coupling AR activation to growth and differentiation, and provide important information on differences between closely-related subtypes.