The volume and electrolyte composition of saliva are dependent on the coordinated activity of ion transport proteins including multiple Na+-dependent mechanisms. Acinar cells employ a combination of Na+/H+ exchangers and Na+/K+/2Cl- cotransporters to drive fluid secretion and related processes such as cell volume maintenance and intracellular pH regulation. Ductal cells then act on acinar cell secretions to conserve NaCl utilizing Na+/H+ exchangers, Na+ channels and other ion transport proteins. The general functional properties of most Na+ transport proteins are understood. However, it is not clear what contribution individual Na+ transport proteins make to the overall secretion process, or which compensatory mechanisms may arise if the activity of a given transporter is perturbed. Thus, Aim 1 will determine which Na+ transport mechanisms are expressed in mouse salivary glands. The level of expression and the localization of different isoforms will be assessed by northern hybridization blots and immunohistochemistry, respectively.
Aim 2 will examine the regulation of the different Na+ transport proteins by secretagogues. It is predicted that functional activity will be modulated for those transporters involved in the formation of saliva during stimulation. The results from the studies proposed in Aims 1 and 2 will provide essential information for predicting the role each transporter plays in the overall fluid secretion process. However, a definitive test of the importance of a given Na+ transport protein can most easily be obtained by studying an animal defective in the expression of that transporter.
In Aim 3 the effects of gene disruption will be examined to determine the functional significance of individual Na+ transport proteins. Mice lacking expression of four different Na+ transport proteins are currently available for study (Na+/H+ exchanger isoforms NHE1, NHE2 and NHE3; Na+/K+/2Cl- cotransporter NKCC1). Mice expressing mutations for three additional Na+ transport proteins present in salivary glands are under development (epithelial Na+ channel ENaC; Na+/H+ exchangers NHE4 and NHE5). This multidisciplinary approach to the functional characterization of Na+ transport proteins will define the mechanisms involved in the production of saliva. The results of these studies will provide a foundation for future studies to analyze the in vivo structure/function relationship of a given Na+ transporter, which may ultimately aid in the development of treatments for various forms of salivary gland dysfunction.
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