BKCa channel phosphorylation and the regulation of smooth muscle contractility

在人体复杂的组织环境中，细胞的功能和相互交流的能力取决于钠、钙、钾和氯等离子进出每个细胞的受控移动。这种运动主要通过嵌入细胞膜的蛋白质复合体形成的充满水的毛孔或通道进行。了解膜离子通道促进组织整体功能反应的机制，如肌肉收缩、激素分泌或神经冲动的传播，一直是医学研究的既定目标。在平滑肌中，钾(K+)外流可能是单个最重要的生理决定因素，通过调节引发收缩的钙内流，决定了平滑肌的功能。在这方面，控制平滑肌细胞K+外流的细胞机制对于调节血管张力和其他含有平滑肌的器官的生理功能具有重要意义。肺、肠道、肾脏、膀胱)。这项研究计划中描述的研究将检查一类特殊的钙和电压敏感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方面发挥主要作用。特别是，我们将阐明这一重要的通道蛋白是如何受到血管内皮细胞衬里产生的化学信号(即一氧化氮)以及临床上开出的硝酸甘油等硝基血管扩张剂的调节的。通过结合基于分子DNA的技术和灵敏的电记录技术来研究这种离子通道的功能特性及其由一氧化氮介导的细胞信号通路的调节，这些技术允许检测单个平滑肌细胞内的通道活动。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，该通道有可能成为治疗哮喘、大小便失禁和血压相关疾病的药物的新靶点。

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.