Beta-Adrenergic Receptors of S49 Lymphoma Cells

描述(由申请人提供)：我们建议继续我们的长期合作 S49淋巴瘤B-肾上腺素能受体(BetaAR)信号通路的研究 细胞。这些细胞提供了一个独特的模型系统，在其中可以表征 特殊成分在BAR增加细胞的这一途径中的作用 环磷酸腺苷(CAMP)、活化蛋白激酶A(PKA)和触发器的水平 最终导致细胞生长停滞和死亡的事件。反馈 信号的调节也是通过G蛋白受体激酶(GRK)进行的 作为PKA。我们的初步研究表明，cAMP介导的S49细胞死亡 细胞通过一种需要PKA的凋亡机制发生。此外，其他 最近的发现暗示了PKA在bar通路中的脱敏作用。 我们建议利用野生型S49细胞和已知的S49细胞变体 BAR反应途径中的损伤(包括S49细胞株，它不 尽管表面上是正常的“上游”信号，但仍会发生细胞凋亡 组件)以确定cAMP生成/PKA激活的作用和机制 参与细胞凋亡及G蛋白受体的作用 激酶和PKA对cAMP参与事件的持续反馈调节 队形和动作。根据其他初步结果，我们还将进行 利用中国仓鼠卵巢(CHO)细胞研究GRK和PKA PKA缺失的CHO细胞。CHO系统中有关受体的数据 脱敏治疗应该是对S49细胞系统研究的补充。通过使用 涉及细胞和分子生物学技术的综合方法， 生物化学和药理学，我们应该获得关于BAR的新信息 发信号。由于BAR在许多器官系统中起着重要生理作用， 尤其是心血管、肾脏和肺脏系统，以及BAR 许多临床重要疾病的药物治疗靶点(例如， 高血压、哮喘、心肌缺血、慢性阻塞性肺 疾病、充血性心力衰竭)，我们的结果可能提供有用的新见解 关于生理调节和药物治疗的问题 刺激或阻止BetaAR信号的物质。此外，结果应该证明 适用于许多其他激素和神经递质受体 到G蛋白。

DESCRIPTION (provided by applicant): We propose to continue our long-standing studies in the B-adrenergic receptor (BetaAR) signalling pathway of S49 lymphoma cells. These cells provide a unique model system in which to characterize the role of particular components in this pathway in which BAR increase cellular levels of cyclic AMP (cAMP), activate protein kinase A (PKA), and trigger events that ultimately lead to growth arrest and death of the cells. Feedback regulation of signalling occurs via a G protein receptor kinase (GRK), as well as PKA. Our preliminary studies indicate that cAMP-mediated cell death of S49 cells occurs via an apoptotic mechanism that requires PKA. Moreover, other recent findings implicate a key role of PKA desensitization of the BAR pathway. We propose to utilize wild-type S49 cells and known variants of S49 cells with lesions in the BAR response pathway (including an S49 cell line which does not undergo apoptosis in spite of apparently normal "upstream" signalling components) to define the role of cAMP generation/PKA activation and mechanisms involved in apoptosis and in addition the contribution of G protein receptor kinase and PKA to ongoing feedback regulation of events involved in cAMP formation and action. Based on other preliminary results, we will also conduct studies of GRK and PKA using Chinese hamster ovary (CHO) cells, both wild-type and PKA-absent CHO cells. Data in the CHO system regarding receptor desensitization should complement studies in the S49 cell system. By using a combined approach that involves techniques of cell and molecular biology, biochemistry, and pharmacology, we should obtain new information regarding BAR signalling. Since BAR play an important physiologic role in many organ systems, in particular the cardiovascular, renal, and pulmonary systems, and BAR are targets of drug therapy in many clinically important disorders (e.g., hypertension, asthma, myocardial ischemia, chronic obstructive pulmonary disease, congestive heart failure), our results may provide useful new insights regarding both physiological regulation as well as drug therapy with agents that stimulate or block BetaAR signalling. Moreover, the results should prove applicable to the many other hormone and neurotransmitter receptors that link to G proteins.