Novel Signaling for Ca2+ and Release in Airway Myocytes

气道肌细胞中 Ca2 和释放的新信号传导

• 批准号: 7214671
• 负责人: YONG-XIAO WANG
• 金额: $ 33.71万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214671
• 关键词: ADP-ribosyl Cyclase; Address; Adrenal Glands; Affect; Asthma; Binding; Biochemical; Biological; Biological Assay; Cells; Cholinergic Agents; Cyclic ADP-Ribose; Data; Dialysis procedure; Excision; FK506; Fluorescence; Generations; Genes; Genetic; Heparin; Inositol; Knock-out; Knockout Mice; Lead; Measurement; Mediating; Mediator of activation protein; Membrane; Methods; Molecular; Molecular Weight; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinics; Muscle; Muscle Cells; Nerve; Neurons; Niacinamide; Numbers; Pancreas; Patch-Clamp Techniques; Phospholipase C; Photometry; Physical Dialysis; Protein Overexpression; Proteins; Radioimmunoassay; Research Personnel; Role; RyR1; RyR2; RyR3; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; System; Tacrolimus Binding Proteins; Testing; asthmatic airway; cell type; chemical genetics; chemokine; cholinergic; genetic manipulation; inositol-1,4,5-triphosphate receptor; knockout gene; methacholine; neuroregulation; novel; novel therapeutics; radioligand; receptor; respiratory smooth muscle; response; simulation; therapeutic target

DESCRIPTION (provided by applicant): Cholinergic nerves provide a predominant neural control of airway smooth muscle cells (ASMCs) through muscarinic receptors. Simulation of these receptors results in the activation of phospholipase C (PLC) and generation of inositol 1,4,5-triphophate (IP3), which induces Ca2+ release through IP3 receptors (IP3Rs). This well-known signaling pathway is important for muscarinic Ca2+ release and contraction in ASMCs. However, our preliminary study, together with previous findings, suggests that muscarinic stimulation may activate ADP-ribosyl cyclase and then produce cyclic ADP-ribose (cADPR), which induces Ca2+ release from the SR by opening RyRs directly and/or indirectly by disassociating FK506 binding protein 12.6 (FKBP12.6) from these Ca2+ release channels, leading to the amplification of muscarinic Ca2+ release and associated contraction in ASMCs. This novel signaling pathway, ADP-ribosyl cyclase-cADPR-FKBP12.6-RyR, may be hyper-functioned in asthma, contributing to the airway muscle Ca2+ and contractile hyperresponsiveness to muscarinic agonists and other numerous spasomogens. To test these hypotheses, we will address the following questions (specific aims): (1) Does cADPR mediate muscarinic Ca2+ release in normal and asthmatic ASMCs? (2) Is FKBP12.6 required for muscarinic Ca2+ release and the target for cADPR in normal and asthmatic ASMCs? and (3) which subtype of RyRs involves muscarinic Ca2+ release and the roles of cADPR and FKBP12.6 in normal and asthmatic ASMCs? These aims will be implemented using simultaneous measurements of Ca2+ sparks or whole-cell [Ca2+]i and membrane currents in freshly disassociated airway myocytes. Genetic manipulations (gene overexpression and knockout), molecular biological and biochemical methods will be also used in this proposal. This study will extend our understanding of the cellular and molecular mechanisms underlying muscarinic Ca2+ release in normal and asthmatic ASMCs, and may also identify novel therapeutic targets for asthma attacks. Since cADPR, FKBP12.6, and/or RyRs are ubiquitously expressed in a variety of cell types, the mechanistic findings from the proposed study will have general biological and pathological significance for various Ca2+-mediated cellular effects.

描述（由申请人提供）：

项目成果

Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells.

• DOI: 10.1152/ajplung.00148.2015
• 发表时间: 2015-12
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Tengyao Song;Q. Hao;Yun‐Min Zheng;Qing‐Hua Liu;Yong-Xiao Wang

Calcineurin upregulates local Ca(2+) signaling through ryanodine receptor-1 in airway smooth muscle cells.

钙调神经磷酸酶通过气道平滑肌细胞中的兰尼定受体 1 上调局部 Ca(2) 信号传导。

• DOI: 10.1152/ajplung.00149.2014
• 发表时间: 2014
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Savoia,CarloP;Liu,Qing-Hua;Zheng,Yun-Min;Yadav,Vishal;Zhang,Zhen;Wu,Ling-Gang;Wang,Yong-Xiao
• 通讯作者: Wang,Yong-Xiao

Potential important roles and signaling mechanisms of YPEL4 in pulmonary diseases.

• DOI: 10.1186/s40169-018-0194-5
• 发表时间: 2018-06-11
• 期刊: Clinical and translational medicine
• 影响因子: 10.6
• 作者: Truong L;Zheng YM;Song T;Tang Y;Wang YX
• 通讯作者: Wang YX

Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

• DOI: 10.1007/978-94-007-0265-3_38
• 发表时间: 2011
• 期刊: ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
• 作者: Wang, Yong-Xiao;Zheng, Yun-Min
• 通讯作者: Zheng, Yun-Min

Methods to measure and analyze ciliary beat activity: Ca2+ influx-mediated cilia mechanosensitivity.

• DOI: 10.1007/s00424-012-1164-1
• 发表时间: 2012-12
• 期刊: Pflugers Archiv : European journal of physiology
• 作者: Li WE;Chen W;Ma YF;Tuo QR;Luo XJ;Zhang T;Sai WB;Liu J;Shen J;Liu ZG;Zheng YM;Wang YX;Ji G;Liu QH
• 通讯作者: Liu QH