BKCa channel phosphorylation and the regulation of smooth muscle contractility

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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.