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Tuning L-Type Ca Channel Activity in Arterial Smooth Muscle by Kv Channel-Mediated Clustering

通过 Kv 通道介导的聚类调节动脉平滑肌中的 L 型 Ca 通道活性

基本信息

批准号：
10210432
负责人：
Luis F Santana
金额：
$ 50.81万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210432
关键词：
Address Affect Animals Arteries Binding Biophysics Blood Pressure Calcium Caliber Calmodulin Cell membrane Cells Coupling Data Development Dihydropyridines Dose Electrophysiology (science)Equilibrium Feedback Female Genes Genetic Models Image Ion Channel Ions Knock-in Mouse Lead Mediating Mediator of activation protein Membrane Membrane Potentials Mesenteric Arteries Modeling Molecular Mus Muscle Cells Muscle Tonus Muscle function Optics Organ Permeability Physiological Physiology Play Potassium Channel Process Property Regulation Resistance Role Sex Differences Signal Transduction Smooth Muscle Smooth Muscle Myocytes Structure System Systemic blood pressure Tail Vascular Smooth Muscle Work constriction experimental study insight large-conductance calcium-activated potassium channels male mutant novel pressure response sensor sex skills spatial relationship voltage

项目摘要

Project Summary Dihydropyridine-sensitive, L-type Cav1.2 and delayed rectifier Kv2.1 channels play critical roles in the regulation of excitability and contraction in arterial smooth muscle. A salient feature of Cav1.2 channels is that they form clusters within which they undergo dynamic, reciprocal interactions that allow functional coupling of adjacent channels and thus amplification of Ca2+ signaling, which is critical to the development of myogenic tone. At present, however, the mechanisms controlling Cav1.2 clustering are unknown. The Trimmer and Santana labs have joined forces to address this fundamental issue. New preliminary data from our labs suggest a novel model that represents a paradigm shift relative to the generally accepted canonical role of Kv2.1, and K+ channels in general, as acting solely as K+ conducting electrical determinants of the intrinsic membrane properties of arterial myocytes. In this model, the Kv2.1 channel has a physical role to increase clustering and thus cooperative gating of Cav1.2 channels. Our data indicate that the balance between the separable electrical and structural roles of Kv2.1 channels fine tunes membrane potential, Cav1.2 clustering, functional coupling of these channels, and hence Ca2+ influx, myogenic tone, and, ultimately, blood pressure. A key finding that underscores the significance of our work is that Kv2.1 expression varies with sex, leading to significant differences in Ca2+ influx and myogenic tone between female and male arterial myocytes. The combination of our complementary skill sets allows us to implement a multi-scale systems approach that involves the use of cellular, molecular, biophysical, imaging, gene editing and whole-animal approaches to rigorously investigate the mechanisms controlling Kv2.1 and Cav1.2 organization, and how they impact cell, organ, and whole-body functions under physiological conditions. The project has three specific aims. Aim 1 is to determine the impact of altered Kv2.1 expression levels on clustering and activity of Cav1.2 channels, and myogenic tone in arterial smooth muscle, and on blood pressure. Aim 2 is to define the mechanisms underlying Kv2.1-mediated regulation of Cav1.2 function. Finally, Aim 3 is to use novel genetic models to define the cell autonomous role of Kv2.1, and its separable conducting and non-conducting functions, in regulating Cav1.2 function, and the myogenic response in arterial smooth muscle cells, and systemic blood pressure. The proposed studies have the potential of transforming our understanding of how ion channels are organized in vascular smooth muscle, and provide insights into how arterial diameter and blood pressure are differentially regulated in females versus males.

项目摘要二氢吡啶敏感的L型Cav1.2和延迟整流Kv2.1通道在细胞凋亡中起关键作用。调节动脉平滑肌的兴奋性和收缩。Cav1.2通道的一个显著特征是，它们形成簇，在簇内它们经历动态的相互作用，邻近通道，从而放大Ca2+信号传导，这对肌源性语气然而，目前，控制Cav1.2聚类的机制尚不清楚。修剪机和桑塔纳实验室已联手解决这一根本问题。我们实验室的新初步数据提出了一个新的模型，代表了一个范式转变相对于普遍接受的规范作用， Kv2.1和K+通道，作为单独作为K+传导的内在电决定因素，动脉肌细胞的膜特性。在该模型中，Kv2.1通道具有增加的物理作用，聚类并因此协作选通Cav1.2信道。我们的数据表明， Kv2.1通道的可分离的电和结构作用微调膜电位，Cav1.2聚类，这些通道的功能耦合，因此Ca2+内流，肌源性紧张，并最终，血压。一一个强调我们工作重要性的关键发现是Kv2.1表达随性别而变化，导致在雌性和雄性动脉肌细胞之间的Ca2+内流和肌源性张力方面存在显著差异。的我们互补的技能组合使我们能够实施多尺度系统方法，涉及使用细胞，分子，生物物理，成像，基因编辑和整体动物方法，严格研究控制Kv2.1和Cav1.2组织的机制，以及它们如何影响细胞，器官和生理条件下的全身功能。该项目有三个具体目标。目标1是确定改变的Kv2.1表达水平对Cav1.2通道的聚类和活性的影响，以及动脉平滑肌中的肌原性张力和血压。目标2是确定潜在的机制 Kv2.1介导的Cav1.2功能调节。最后，目标3是使用新的遗传模型来定义细胞 Kv2.1的自主作用及其可分离的传导和非传导功能，在调节Cav1.2中功能和动脉平滑肌细胞中的生肌反应以及全身血压。的提出的研究有可能改变我们对离子通道如何组织的理解，血管平滑肌，并提供动脉直径和血压如何差异的见解女性与男性之间的调节。