Persistent Calcium Sparklets in Vascular Smooth Muscle

血管平滑肌中持续存在钙火花

• 批准号: 7390390
• 负责人: Luis F Santana
• 金额: $ 39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390390
• 关键词: Angiotensin II; Angiotensins; Biological; Blood Vessels; Calcium; Cells; Condition; Cytosol; Data; Dihydropyridines; Disease; Event; Figs - dietary; Functional disorder; Gene Expression; Genes; Goals; Health; Hypertension; Imaging Techniques; Individual; Knock-out; L-Type Calcium Channels; Mediating; Membrane; Membrane Potentials; Methods; Modality; Modeling; Molecular; Muscle Cells; Optics; Physiological; Physiological Processes; Play; Probability; Process; Property; Regulation; Relative (related person); Research Personnel; Role; Signal Transduction; Site; Smooth Muscle; Techniques; Testing; Transcriptional Activation; Transgenic Organisms; Up-Regulation; Vascular Smooth Muscle; Vasoconstrictor Agents; Work; base; cerebral artery; dihydropyridine; novel; patch clamp; programs; research study; vasoactive agent; voltage

DESCRIPTION (provided by applicant): Calcium influx via dihydropyridine-sensitive, voltage-gated L-type calcium channels plays a crucial role in the regulation of excitability, contraction, and gene expression in arterial smooth muscle. Our recent discovery that small clusters of L-type calcium channels can operate in a "persistent" gating mode that create sites of nearly continual calcium influx (called "persistent calcium sparklets") in smooth muscle has led to a paradigm shift, whereby calcium influx in these cells is predominantly controlled by this process in combination with rare voltage-dependent openings of individual L-type calcium channels. However, the role of persistent calcium sparklets on the regulation of local and global intracellular calcium as well as the molecular mechanisms underlying the activation and modulation of these calcium influx events in smooth muscle under physiological and pathophysiological conditions is virtually unknown. The proposed work will use new methods developed by our group to define the biophysical properties and functional roles of calcium sparklets in cerebral artery smooth muscle. Our preliminary results suggest that all proposed experiments are feasible and will provide important new information. The proposed work seeks to test three novel hypotheses. In Specific Aim 1, we will test the hypothesis that calcium influx via calcium sparklets contributes to changes in local and global intracellular calcium concentration. The experiments in Specific Aim 2 will test the hypothesis that Cav1.2 channels underlie calcium sparklets in arterial smooth muscle. Finally, in Specific Aim 3, we build on the work in the previous two Specific Aims and test the hypothesis that persistent calcium sparklet activity is increased during hypertension. This work should provide the first integrated view of calcium sparklet-mediated signaling and their role in modulating cerebral arteries function and significantly enhance our understanding of arterial function in health and disease.

描述（由申请人提供）：通过二氢吡啶敏感的，电源门控的L型钙通道的流入钙在调节动脉平滑肌中的兴奋性，收缩和基因表达中起着至关重要的作用。我们最近发现，L型钙通道的一小簇可以以“持续”的彩门模式运行，该模式在平滑肌中创建几乎连续的钙涌入（称为“持续性钙火花”）的位点导致范式转移，从而使这些细胞中的钙涌入这些细胞中的钙涌入在这些过程中与稀有频道相结合的速度相差，使得依赖于差异。然而，持续性钙火花在调节局部和全球细胞内钙的调节以及在生理和病理生理条件下平滑肌中这些钙涌入事件的激活和调节的分子机制几乎是未知的。拟议的工作将使用我们小组开发的新方法来定义脑动脉平滑肌中钙火花的生物物理特性和功能作用。我们的初步结果表明，所有提出的实验都是可行的，将提供重要的新信息。拟议的工作旨在检验三个新的假设。在特定目标1中，我们将测试以下假设：钙通过钙火花钙的流入有助于局部和全局细胞内钙浓度的变化。特定目标2中的实验将检验以下假设：Cav1.2通道是动脉平滑肌中钙火花基础的基础。最后，在特定的目标3中，我们以前两个特定目标的工作为基础，并检验了高血压期间持续的钙火花活动增加的假设。这项工作应提供钙火花介导的信号传导及其在调节脑动脉功能中的作用的首次综合视图，并显着增强我们对健康和疾病动脉功能的理解。