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(由申请人提供：血管活性多肽内皮素-1(ET1)通过不同的信号通路刺激血管平滑肌收缩和促进肥大。此前，ET1可以升高血管平滑肌细胞(VSMC)中的cAMP，但由于作用不大，其功能后果尚未被探索。我们发现，尽管ET1对cAMP的影响很小，但它可以显著激活蛋白激酶A(PKA)-一种被认为与抑制VSMC收缩和增殖有关的效应酶。然而，我们的初步数据表明，在VSMC中，ET1诱导的PKA激活与β-激动剂异丙肾上腺素(ISO)诱导的PKA激活在几个关键方面不同：(I)ET1诱导的PKA激活持续时间比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激活没有这种作用；以及(Iii)当被ET1激活时，PKA磷酸化一系列蛋白质，其中一些不同于ISO刺激时被PKA磷酸化的蛋白质。这些初步数据表明，PKA的激活方式(ET1和ISO)深刻地影响着VSMC中PKA激活的一些功能后果。本研究的主要目的是：a)明确ET1激活PKA的信号机制以及它们与ISO诱导的信号机制有何不同；b)开始了解PKA如何促进ET1诱导的VSMC肥大，以及为什么它在ISO激活时不这样做。为了实现我们的主要目标，我们提出了三个特定的目标：1)确定ET1在VSMC中瞬时激活PKA的机制；2)检测蛋白激酶B/Akt是否以依赖于PKA的方式被ET1磷酸化和激活；以及3)以依赖于PKA的方式识别被ET1或ISO差异磷酸化的蛋白质。这项研究具有基础性和实际意义，因为它可能揭示PKA激活的新的激动剂特异性后果，并可能导致更好地理解高血压、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.

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

Actin cytoskeleton in myofibroblast differentiation: ultrastructure defining form and driving function.

• DOI: 10.1016/j.trsl.2011.05.004
• 发表时间: 2011-10
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Sandbo N;Dulin N
• 通讯作者: Dulin N

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。

• DOI: 10.1016/j.cardiores.2007.01.011
• 发表时间: 2007
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Sandbo,Nathan;Taurin,Sebastien;Yau,DouglasM;Kregel,Steven;Mitchell,Richard;Dulin,NickolaiO
• 通讯作者: Dulin,NickolaiO