Regulation of Calcium-activated Chloride Conductance in Smooth Muscle Vasculature

平滑肌脉管系统中钙激活氯化物电导的调节

• 批准号: 8035349
• 负责人: Ramon Jose Ayon
• 金额: $ 2.81万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2012-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035349
• 关键词: American Heart Association; Blood Vessels; Calcineurin; Calcium; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Cessation of life; Chloride Channels; Chloride Ion; Chlorides; Development; Epithelial; Etiology; Goals; Infarction; Ion Channel; Lead; Membrane; Myocardial; Myocardium; Neurons; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation Site; Play; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Serine/Threonine Phosphatase; Protein phosphatase; Pulmonary Hypertension; Pulmonary artery structure; Regulation; Relative (related person); Research Project Grants; Role; Smooth Muscle; Smooth Muscle Myocytes; Specificity; Stroke; Techniques; United States; Up-Regulation; Vascular Smooth Muscle; Work; calmodulin-dependent protein kinase II; improved; novel; patch clamp

DESCRIPTION (provided by applicant): Calcium-activated chloride channels (Clca) are widely expressed in numerous cells including epithelial, neuronal, cardiac and smooth muscle cells (SMC). CICa have been implicated in many important cellular functions such as epithelial secretion, membrane excitability in neurons and cardiac muscle as well as regulation of smooth muscle vascular tone. As a result of CICa expression in pulmonary artery smooth muscle cells (PASMC), there is a possibility that these channels may participate in the etiology of various forms of pulmonary hypertension (PH). Recent work by our group has provided evidence for the modulation of calcium-activated chloride currents (Icuca)) through phoshorylation and dephosphorylation by calmodulin- dependent protein kinase II (CaMKII) and Ca2+dependent Calcineurin (CaN; PP2B) respectively in arterial SMC. As a result of the serine/threonine phosphatase CaN involvement in up-regulation of Clca conductance, it is possible that there may be other phophatases contributing in up-regulation their activity as well. In rabbit pulmonary artery SMCs, the major goals of this research project are to: 1) determine the relative role of CaMKII and CaN in the regulation of CICa channels under static and dynamic intracellular calcium levels; 2) determine the structural determinants conferring specificity of CaN Aa over CaN A(3 in the regulation of CICa; and 3) examine the possible involvement of other serine/threonine phosphatases (PP1/PP2A) in the modulation of lCi(ca)- To accomplish this task, a variety of techniques will be implemented, including the use of pharmacological agents to inhibit protein phosphatases under whole-cell patch clamp conditions in rabbit PASMC to determine the relative contribution of PP1 and PP2A in CICa conductance. This technique will also prove to be useful in determining whether CaN and the other(s) ser/thr phosphatases target a common or distinct phosphorylation site to modulate Cardiovascular disease (CVD) remains to be one of the largest killers in the United States. According to the American Heart Association, in 2003 CVD was the underlying cause of death for more than 37% of all deaths in the United States. Since ion channels play an important role in the regulation of vascular tone, it is our hope that a better understanding of the underlying mechanisms of ion channels (like Clca) in the cardiovascular system will lead to novel vascular targets for the development of new drugs to improve the conditions of patients suffering from CVDs such as PH, stroke, myocardial angina and infarctions.

描述（由申请人提供）：钙活化的氯化物通道（CLCA）在包括上皮，神经元，心脏和平滑肌细胞（SMC）在内的许多细胞中广泛表达。 CICA与许多重要的细胞功能有关，例如上皮分泌，神经元和心肌的膜兴奋性以及平滑肌血管张力的调节。由于CICA在肺动脉平滑肌细胞中表达（PASMC），这些通道可能参与各种形式的肺动脉高压（pH）的病因。我们小组的最新工作为通过钙调蛋白依赖性蛋白激酶II（CAMKII）和Ca2+依赖性钙钙蛋白（CAN; pp2b）分别通过钙调蛋白依赖性蛋白激酶II（CAMKII）II（CAMKII）II（CAN; PP2B）分别在钙化蛋白依赖性蛋白激酶II（CAMKII）和钙磷酸化中调节了钙激活的氯离子电流（ICUCA）的最新工作。由于丝氨酸/苏氨酸磷酸酶可能参与CLCA电导的上调，因此可能有其他磷酸蛋白酶也有助于上调其活性。在兔肺动脉SMC中，该研究项目的主要目标是：1）确定CAMKII和CAN在静态和动态细胞内钙水平下CICA通道中的相对作用； 2）确定在CAN上授予特异性特异性的结构决定因素（3中的3中； 3）检查其他丝氨酸/苏氨酸磷酸酶（PP1/PP2A）可能参与LCI（CA）（CA）的调节 - 在这些任务中的使用，包括各种派别的派别，将其用于隔离式派别，以构架的方式适用于lci（ca）。兔PASMC的条件以确定pp1和pp2a在CICA电导中的相对贡献。该技术还将被证明可用于确定CAN和其他（S）Ser/Thr磷酸酶是否针对常见或不同的磷酸化位点来调节心血管疾病（CVD）仍然是美国最大的杀手之一。根据美国心脏协会的数据，2003年，CVD是美国所有死亡人数中37％以上的死亡原因。由于离子频道在血管张力调节中起着重要作用，因此我们希望对心血管系统中离子通道（例如CLCA）的潜在机制有更好的了解将为开发新药的新型血管靶标，以改善患有CVD的患者状况，例如PH，Stroke，Stroke，Stroke，Stroke，Stroke，Stroke，Stroke，Stroke，肌肉症和Infararcartials和Infararcartions。