Activation of protein kinase A by endothelin-1

内皮素 1 激活蛋白激酶 A

• 批准号: 7623843
• 负责人: NICKOLAI O DULIN
• 金额: $ 28.92万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623843
• 关键词: 1-Phosphatidylinositol 3-Kinase; ADRBK1 gene; Adenoviruses; Adenylate Cyclase; Affect; Agonist; Atherosclerosis; Blood Vessels; Ca(2+)-Calmodulin Dependent Protein Kinase; Calmodulin; Cell Survival; Cell model; Cells; Complement; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Digestion; Dinoprostone; Electrophoresis; Endothelin-1; Enzymes; Genes; Growth; Hydrolysis; Hypertension; Hypertrophy; Immunoprecipitation; Isoproterenol; Lead; Mass Spectrum Analysis; Mediating; Mitogen-Activated Protein Kinases; Molecular; Mus; Muscle Contraction; Nitric Oxide Synthase; Pathogenesis; Peptides; Phospholipase A2; Phosphorylation; Production; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Silver Staining; Smooth Muscle Myocytes; Testing; Time; Transducin; Trypsin; Vascular Smooth Muscle; Vasospasm; calmodulin-dependent protein kinase II; cell growth; phosphoric diester hydrolase; prevent; programs; response; restenosis

DESCRIPTION (provided by applicant: The vasoactive peptide endothelin-1 (ET1) stimulates contraction and promotes hypertrophy of vascular smooth muscle, through diverse signaling pathways. Previously, it has been variably reported that ET1 can elevate cAMP in vascular smooth muscle cells (VSMC), but the functional consequences of this elevation have not be explored because the effects were modest. We have found that despite its minimal effect on cAMP, ET1 can dramatically activate protein kinase A (PKA) - an effector enzyme thought to be implicated in inhibition of VSMC contraction and proliferation. However, our preliminary data indicates that in VSMC, PKA activation by ET1 differs from that induced by beta-agonist, isoproterenol (ISO), in several key ways: (i) the duration of PKA activation by ET1 is much shorter than that induced by ISO; (ii) ET1-induced PKA activation promotes hypertrophic growth, whereas ISO-induced PKA activation has no such effect; and (iii) when activated by ET1, PKA phosphorylates a complement of proteins, some of which are different from those phosphorylated by PKA during ISO stimulation. These preliminary data indicate that the mode of PKA activation (ET1 vs. ISO) profoundly influences some of the functional consequences of PKA activation in VSMC. The major objective of this proposal is a) to identify the signaling mechanisms of PKA activation by ET1 and how they are different from those induced by ISO, and b) to begin understanding how PKA promotes ET1-induced hypertrophy of VSMC and why it does not do this when activated by ISO. To achieve our major objective, we propose three specific aims: 1) identify the mechanisms of transient PKA activation by ET1 in VSMC; 2) examine whether protein kinase B/Akt is phosphorylated and activated by ET1 in a PKA-dependent manner; and 3) identify the proteins that are differentially phosphorylated by ET1 or ISO in a PKA-dependent manner. This study is of fundamental and practical importance, as it may uncover the new agonist-specific consequences of PKA activation and may lead to a better understanding the pathogenesis of hypertension, atherosclerosis, restenosis and vasospasm.

描述（申请人提供：血管活性肽内皮素-1（ET1）通过多种信号通路刺激血管平滑肌收缩并促进血管肥大。此前，有不同报道称ET1可以提高血管平滑肌细胞（VSMC）中的cAMP ，但尚未探讨这种升高的功能后果，因为其影响不大。我们发现，尽管 ET1 对 cAMP 的影响很小，但它可以显着激活蛋白激酶 A (PKA)。 - 一种效应酶，被认为与抑制 VSMC 收缩和增殖有关。然而，我们的初步数据表明，在 VSMC 中，ET1 激活的 PKA 与 β 激动剂异丙肾上腺素 (ISO) 诱导的激活在几个关键方面有所不同：( i) ET1 激活 PKA 的持续时间比 ISO 诱导的短得多； (ii) ET1 诱导的 PKA 激活促进肥大生长，而 ISO 诱导的 PKA 激活则没有这种作用； (iii) 当被 ET1 激活时，PKA 磷酸化一系列蛋白质，其中一些蛋白质与 ISO 刺激期间 PKA 磷酸化的蛋白质不同。这些初步数据表明 PKA 激活模式（ET1 与 ISO）深刻影响 VSMC 中 PKA 激活的一些功能后果。该提案的主要目标是 a) 确定 ET1 激活 PKA 的信号传导机制以及它们与 ISO 诱导的信号传导机制有何不同，b) 开始了解 PKA 如何促进 ET1 诱导的 VSMC 肥大以及为什么不促进由 ISO 激活时执行此操作。为了实现我们的主要目标，我们提出了三个具体目标：1）确定VSMC中ET1短暂激活PKA的机制； 2)检测蛋白激酶B/Akt是否被ET1以PKA依赖性方式磷酸化和激活； 3) 鉴定以 PKA 依赖性方式被 ET1 或 ISO 差异磷酸化的蛋白质。这项研究具有基础和实际意义，因为它可能揭示 PKA 激活的新的激动剂特异性后果，并可能导致更好地了解高血压、动脉粥样硬化、再狭窄和血管痉挛的发病机制。

项目成果

Phosphorylation of beta-catenin by PKA promotes ATP-induced proliferation of vascular smooth muscle cells.

PKA 磷酸化 β-连环蛋白可促进 ATP 诱导的血管平滑肌细胞增殖。

• DOI: 10.1152/ajpcell.00096.2008
• 发表时间: 2008-05-01
• 期刊: American journal of physiology. Cell physiology
• 作者: S. Taurin;N. S;bo;bo;Douglas M. Yau;N. Sethakorn;N. Dulin
• 通讯作者: N. Dulin

Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase.

环 AMP 依赖性蛋白激酶对 β-连环蛋白进行磷酸化。

• 发表时间: 2024-09-13
• 期刊: The Journal of biological chemistry
• 作者: S. Taurin;N. S;bo;bo;Yimin Qin;D. Browning;N. Dulin
• 通讯作者: N. Dulin

Gbetagamma-mediated prostacyclin production and cAMP-dependent protein kinase activation by endothelin-1 promotes vascular smooth muscle cell hypertrophy through inhibition of glycogen synthase kinase-3.

Gbetagamma 介导的前列环素产生和内皮素 1 的 cAMP 依赖性蛋白激酶激活通过抑制糖原合酶激酶 3 促进血管平滑肌细胞肥大。

• 发表时间: 2007-07-06
• 作者: Taurin, Sebastien;Hogarth, Kyle;Sandbo, Nathan;Yau, Douglas M;Dulin, Nickolai O
• 通讯作者: Dulin, Nickolai O

Critical role of serum response factor in pulmonary myofibroblast differentiation induced by TGF-beta.

血清反应因子在 TGF-β 诱导的肺肌成纤维细胞分化中的关键作用。

• DOI: 10.1165/rcmb.2008-0288oc
• 发表时间: 2009-01-16
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: N. S;bo;bo;Steven Kregel;S. Taurin;S. Bhorade;N. Dulin
• 通讯作者: N. Dulin

Downregulation of smooth muscle alpha-actin expression by bacterial lipopolysaccharide.

细菌脂多糖下调平滑肌α-肌动蛋白表达。

• 发表时间: 2007-05-01
• 影响因子: 10.8
• 作者: Sandbo, Nathan;Taurin, Sebastien;Yau, Douglas M;Kregel, Steven;Mitchell, Richard;Dulin, Nickolai O
• 通讯作者: Dulin, Nickolai O