Ca2+ Sparks as Regulators of Airway Contractility

Ca2 Sparks 作为气道收缩性的调节剂

• 批准号: 7228897
• 负责人: Ronghua ZhuGe
• 金额: $ 30.15万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-10 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228897
• 关键词: Address; Aging; Asthma; Attention; Biophysics; Blood Pressure; Brain; Cardiac; Cardiomegaly; Cell membrane; Cells; Characteristics; Complement component C1s; Comprehension; Coronary; Coronary artery; Coupling; Development; Disease; Elevation; Event; Failure; Figs - dietary; Functional disorder; Generations; Goals; Health; Heart failure; Hyperactive behavior; Hypertension; Image; Imaging Techniques; In Situ; Intracellular Membranes; Ion Channel; Knockout Mice; Knowledge; Lead; Life; Localized; Lung; Membrane; Membrane Potentials; Methods; Mitochondria; Molecular; Mus; Muscle Contraction; Numbers; Pathogenesis; Personal Satisfaction; Physiological; Physiology; Play; Preparation; Regulation; Relaxation; Research; Role; Role playing therapy; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Transduction; Slice; Smooth Muscle; Smooth Muscle Myocytes; Spasm; Speed; Testing; Transgenic Organisms; Vascular Smooth Muscle; Work; digital; insight; intracellular protein transport; large-conductance calcium-activated potassium channels; mouse model; novel; novel therapeutics; patch clamp; protein localization location; respiratory smooth muscle; sensor; spatial relationship; therapeutic target; voltage

DESCRIPTION (provided by applicant): This project seeks to understand the mechanisms by which the contractility of airway smooth muscle (ASM) is controlled and regulated. The present proposal focuses on the highly localized and short-lived Ca2+ events (Ca2+ sparks), resulting from the opening of ryanodine receptors (RyRs) in the sarcoplasmic reticulum membrane, and their interactions with nearby Ca2+-activated ion channels in the plasma membrane. As in vascular smooth muscle, Ca2+ sparks activate a small number of large-conductance K+ (BK) channels in the spark microdomain to generate spontaneous transient outward currents (STOCs) which hyperpolarize the membrane in ASM. Recently we have identified another important target of Ca2+ sparks in ASM, i.e. Ca2+-activated CI- (CIca) channels which cause spontaneous transient inward currents (STICs) and thus depolarize the membrane. Accordingly, the central hypothesis of this proposal is that Ca2+ sparks coordinate the activation of membrane channels to regulate airway contractility. An integrated approach using high-speed digital Ca2+ imaging with simultaneous patch-clamping, and also 2D and 3D protein localization, will be applied using normal and transgenic mouse models. Furthermore, a physiological airway preparation, i.e., lung slices, will be employed to investigate the role of Ca2+ sparks in regulating contractility of airways themselves. Our specific objectives are to uncover the biophysics of RyRs underlying Ca2+ sparks using our newly developed signal mass approach (Aim 1); to determine the functional and spatial relationships of RyRs to BK channels and CIca channels (Aims 2 and 3); and to determine the physiological role of Ca2+ sparks in airways (Aim 4). We expect that these studies will provide new knowledge which could lead to development of novel therapeutic approaches for asthma and other bronchospasitc disorders.

描述（由申请人提供）：该项目旨在了解控制和调节气道平滑肌（ASM）收缩力的机制。目前的提案重点关注高度局部和短暂的 Ca2+ 事件（Ca2+ 火花），该事件是由于肌浆网膜中兰尼碱受体 (RyRs) 的开放引起的，以及它们与质膜中附近 Ca2+ 激活的离子通道的相互作用。与血管平滑肌一样，Ca2+ 火花激活火花微区中的少量大电导 K+ (BK) 通道，产生自发瞬态外向电流 (STOC)，使 ASM 中的膜超极化。最近，我们发现了 ASM 中 Ca2+ 火花的另一个重要目标，即 Ca2+ 激活的 CI- (CIca) 通道，它会引起自发瞬态内向电流 (STIC)，从而使膜去极化。因此，该提议的中心假设是Ca2+火花协调膜通道的激活以调节气道收缩性。使用高速数字 Ca2+ 成像和同步膜片钳以及 2D 和 3D 蛋白质定位的综合方法将应用于正常和转基因小鼠模型。此外，还将采用生理气道准备，即肺切片，来研究 Ca2+ 火花在调节气道本身收缩性中的作用。我们的具体目标是使用我们新开发的信号质量方法揭示 Ca2+ 火花背后的 RyRs 生物物理学（目标 1）；确定 RyR 与 BK 通道和 CIca 通道的功能和空间关系（目标 2 和 3）；并确定 Ca2+ 火花在气道中的生理作用（目标 4）。我们期望这些研究将提供新知识，从而开发出治疗哮喘和其他支气管痉挛疾病的新方法。

项目成果

Catecholamine exocytosis during low frequency stimulation in mouse adrenal chromaffin cells is primarily asynchronous and controlled by the novel mechanism of Ca2+ syntilla suppression.

小鼠肾上腺嗜铬细胞低频刺激期间儿茶酚胺的胞吐作用主要是异步的，并受 Ca2 Syntilla 抑制的新机制控制。

• 发表时间: 2014-11-01
• 作者: Lefkowitz, Jason J;DeCrescenzo, Valerie;Duan, Kailai;Bellve, Karl D;Fogarty, Kevin E;Walsh Jr, John V;ZhuGe, Ronghua
• 通讯作者: ZhuGe, Ronghua

A close association of RyRs with highly dense clusters of Ca2+-activated Cl- channels underlies the activation of STICs by Ca2+ sparks in mouse airway smooth muscle.

RyR 与高密度 Ca2 激活 Cl 通道簇的密切关联是小鼠气道平滑肌中 Ca2 火花激活 STIC 的基础。

• 发表时间: 2008-07
• 作者: Bao, Rongfeng;Lifshitz, Lawrence M;Tuft, Richard A;Bellvé, Karl;Fogarty, Kevin E;ZhuGe, Ronghua
• 通讯作者: ZhuGe, Ronghua

A C-terminally truncated mouse Best3 splice variant targets and alters the ion balance in lysosome-endosome hybrids and the endoplasmic reticulum.

C 端截短的小鼠 Best3 剪接变体靶向并改变溶酶体-内体杂合体和内质网中的离子平衡。

• 发表时间: 2016-06-06
• 影响因子: 4.6
• 作者: Wu, Lichang;Sun, Yu;Ma, Liqiao;Zhu, Jun;Zhang, Baoxia;Pan, Qingjie;Li, Yuyin;Liu, Huanqi;Diao, Aipo;Li, Yinchuan
• 通讯作者: Li, Yinchuan

Spatial organization of RYRs and BK channels underlying the activation of STOCs by Ca(2+) sparks in airway myocytes.

RYR 和 BK 通道的空间组织是气道肌细胞中 Ca(2 ) 火花激活 STOC 的基础。

• 发表时间: 2011-08
• 作者: Lifshitz, Lawrence M;Carmichael, Jeffrey D;Lai, F Anthony;Sorrentino, Vincenzo;Bellvé, Karl;Fogarty, Kevin E;ZhuGe, Ronghua
• 通讯作者: ZhuGe, Ronghua

The transmembrane protein 16A Ca(2+)-activated Cl- channel in airway smooth muscle contributes to airway hyperresponsiveness.

气道平滑肌中跨膜蛋白 16A Ca(2 ) 激活的 Cl 通道有助于气道高反应性。

• DOI: 10.1164/rccm.201207-1303oc
• 发表时间: 2013-02-15
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Cheng;Yinchuan Li;Wei Zhao;Lawrence M. Lifshitz;Hequan Li;B. Harfe;Min;R. Zhuge
• 通讯作者: R. Zhuge