Transepithelial chloride movement acts as the driving force for fluid secretion, a critical event in the efficient delivery of salivary proteins to the oral cavity. Chloride channels are the primary chloride efflux pathway in salivary glands and thus are a key site of regulation for stimulation-induced fluid movement, pHi homeostasis and cell volume. The Principal Investigator has identified two distinct types of chloride channels in rat parotid acinar cells, the Ca2+-dependent and volume- sensitive chloride channels. Elucidating the structure-function relationships of the chloride channels associated with fluid secretion is essential for understanding salivary gland dysfunction caused by a myriad of perturbations including postradiation- and drug-induced xerostomia, Sjogren's disease or chloride transporting defects such as cystic fibrosis. However, a thorough understanding of the mechanisms and the regulation of chloride translocation via channel proteins is lacking. Plans are to study the function of chloride channels in salivary acinar cells as follows: 1) characterize clones from rat salivary gland cDNA libraries encoding the chloride channels to determine the degree of homology with other chloride channel proteins and to identify potentially important domains for channel activity and function. 2) determine the kinetic properties of chloride channel proteins in salivary acinar cells. These studies will provide information about transport mechanisms and will reveal possible similarities to proteins in other tissues. The use of patch clamp studies will yield the number of channels/cell and chloride current/cell which will aid in defining the detailed role chloride ions play in secretion. 3) examine the regulation of chloride conductance by Ca2+-, cAMP-and pH-dependent processes. 4) assess the functional significance of chloride channels in salivary acinar cells by determining their tissue distribution and subcellular location. A combination of pharmacological and antisense inhibition studies will verify the importance of these channels to the fluid secretion process. Insight gained from these studies may therefore aid in developing rationales for preventing and/or treating salivary gland dysfunctions by enhancing the remaining functional parenchyma and for designing novel secretory drugs that stimulate chloride-driven secretion.
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