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1 Department of Biology, Indiana University - Purdue University at Indianapolis, Indianapolis, IN, USA
2 Division of Nephrology, Indiana University School of Medicine and Richard Roudebusch VAMC, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: bblazer{at}iupui.edu.
In the distal tubule, Na+ resorption is mediated by epithelial Na+ channels (ENaC). Hormones such as aldosterone, vasopressin and insulin modulate ENaC membrane targeting, assembly and/or kinetic activity thereby regulating salt and water homeostasis. Insulin binds to a receptor on the basal membrane to initiate a signal transduction cascade that rapidly results in an increase in apical membrane ENaCs. Current models of this signaling pathway envision diffusion of signaling intermediates from the basal to apical membrane. This necessitates diffusion of several high-molecular weight signaling elements across a three-dimensional space. Transduction of the insulin signal involves the phosphoinositide pathway but how and where this lipid-based signaling pathway controls ENaC activity is not known. We used tagged channels, biosensor lipid probes and intra-vital imaging to investigate the role of lipids in insulin stimulated Na+ flux. Insulin-stimulated delivery of intracellular ENaC to apical membranes was concurrent with plasma membrane-limited changes in lipid composition. Notably, in response to insulin, phosphatidylinositol 3,4,5 trisphosphate (PIP3) was formed in the basolateral membrane and rapidly diffused within the bilayer, crossing the tight junction, to enter the apical membrane. This novel signaling pathway takes advantage of the fact that the lipids of the plasma membrane's inner leaflet are not constrained by the tight junction. Therefore, diffusion of PIP3, as a signal transduction intermediate, occurs within a planar surface thus facilitating swift responses as well as confining and controlling the signaling pathway.
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