BKCa channel phosphorylation and the regulation of smooth muscle contractility

BKCa 通道磷酸化与平滑肌收缩力的调节

• 批准号: 312240-2009
• 负责人: Braun, Andrew
• 金额: $ 2.33万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=498090
• 关键词: BKCa; channel; phosphorylation; regulation; smooth

The ability of cells to function and communicate with one another in the complex tissue environments of the body is dependent upon the controlled movement of ions such as sodium, calcium, potassium and chloride, into and out of each individual cell. Such movement occurs primarily through water-filled pores or channels formed by protein complexes embedded in cell membranes. Understanding the mechanisms by which membrane ion channels contribute to the gross functional responses of a tissue, such as muscle contraction, secretion of hormones, or the propagation of nervous impulses, has been a long-established goal of medical research. In smooth muscle, potassium (K+) efflux may be the single most important physiologic determinant of smooth muscle function, by regulating the influx of calcium that triggers contraction. In this respect, the cellular mechanisms controlling K+ efflux in smooth muscle cells are of fundamental importance to the regulation of vascular tone and the physiologic functions of other smooth muscle-containing organs (eg. lungs, gut, kidney, bladder). The studies described in this research proposal will examine the molecular properties and regulation of a special class of calcium- and voltage-sensitive K+ channel that plays a major role in the control of systemic blood pressure, lung airway dilation and bladder filling. In particular, we will elucidate how this important channel protein is regulated by chemical signals (i.e. nitric oxide) produced by the endothelial lining of blood vessels, along with clinically prescribed nitrovasodilators, such as nitroglycerin. The functional properties of this ion channel and its regulation by nitric oxide-mediated cell signaling pathways will be studied by combining molecular DNA-based technology with sensitive electrical recording techniques that allow detection of channel activity within a single smooth muscle cell. These proposed studies will provide important, new insight into the structure, function and modulation of an ion channel with potential as a novel therapeutic target for drugs in the treatment of asthma, incontinence and blood pressure-related illnesses.

细胞在身体的复杂组织环境中发挥功能和相互通信的能力取决于离子如钠、钙、钾和氯进出每个单个细胞的受控运动。 这种运动主要通过由嵌入细胞膜中的蛋白质复合物形成的充满水的孔或通道发生。了解膜离子通道促进组织的总体功能反应的机制，例如肌肉收缩、激素分泌或神经冲动的传播，一直是医学研究的长期目标。 在平滑肌中，钾（K+）流出可能是平滑肌功能的单一最重要的生理决定因素，通过调节触发收缩的钙内流。 在这方面，控制平滑肌细胞中K+流出的细胞机制对于调节血管张力和其他含平滑肌器官（例如，血管平滑肌细胞）的生理功能具有根本重要性。肺、肠、肾、膀胱）。 本研究提案中描述的研究将检查一类特殊的钙和电压敏感性K+通道的分子特性和调节，该通道在控制全身血压，肺气道扩张和膀胱充盈中起着重要作用。特别是，我们将阐明这种重要的通道蛋白是如何调节的化学信号（即一氧化氮）所产生的血管内皮衬里，沿着与临床处方的硝酸血管扩张剂，如硝酸甘油。该离子通道的功能特性及其通过一氧化氮介导的细胞信号传导途径的调节将通过结合基于分子DNA的技术与灵敏的电记录技术来研究，该技术允许检测单个平滑肌细胞内的通道活性。 这些拟议的研究将为离子通道的结构、功能和调节提供重要的新见解，该离子通道有可能成为治疗哮喘、尿失禁和血压相关疾病的药物的新治疗靶点。