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(由申请者提供)：该项目旨在了解控制和调节呼吸道平滑肌(ASM)收缩的机制。目前的研究集中在肌浆网膜上兰尼定受体(RyRs)的开放引起的高度局部化和短暂的钙事件(钙火花)，以及它们与质膜上附近的钙激活离子通道的相互作用。与血管平滑肌一样，钙火花激活火花微区的少量大电导K+(BK)通道，产生自发的瞬时外向电流(STOCs)，从而使ASM膜超极化。最近，我们发现了ASM中钙离子放电的另一个重要靶点，即钙激活的CI-(CICA)通道，它能引起自发的瞬时内向电流(STICs)，从而使膜去极化。因此，这一建议的中心假设是，钙火花协调膜通道的激活，以调节呼吸道的收缩能力。一种使用高速数字钙离子成像和同时膜片钳以及2D和3D蛋白质定位的综合方法将在正常和转基因小鼠模型中应用。此外，生理性的呼吸道准备，即肺切片，将被用来研究钙离子火花在调节呼吸道本身收缩性能方面的作用。我们的具体目标是使用我们新开发的信号质量方法(目标1)揭示RyRs的生物物理基础(目标1)；确定RyRs与BK通道和CICA通道的功能和空间关系(目标2和3)；以及确定钙火花在呼吸道中的生理作用(目标4)。我们希望这些研究将提供新的知识，可能导致开发新的治疗方法来治疗哮喘和其他支气管炎疾病。

项目成果

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

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

Suppression of Ca2+ syntillas increases spontaneous exocytosis in mouse adrenal chromaffin cells.

• DOI: 10.1085/jgp.200910285
• 发表时间: 2009-10
• 期刊: The Journal of general physiology
• 作者: Lefkowitz JJ;Fogarty KE;Lifshitz LM;Bellve KD;Tuft RA;ZhuGe R;Walsh JV Jr;De Crescenzo V
• 通讯作者: De Crescenzo V

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.

• DOI: 10.1085/jgp.200709933
• 发表时间: 2008-07
• 期刊: The Journal of general physiology
• 作者: Bao R;Lifshitz LM;Tuft RA;Bellvé K;Fogarty KE;ZhuGe R
• 通讯作者: ZhuGe R

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

• DOI: 10.1038/srep27332
• 发表时间: 2016-06-06
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Wu L;Sun Y;Ma L;Zhu J;Zhang B;Pan Q;Li Y;Liu H;Diao A;Li Y
• 通讯作者: Li Y