The epithelial sodium channel subunit ( ENaC) alternatively spliced form "b" in Dahl rats: What's next?

Abstract

Background. The amiloride-sensitive Epithelial Sodium Channel (ENaC) is critical in maintaining Na+ balance, extracellular fluid volume and long term blood pressure control. ENaC is composed of three main subunits α,β , & γ. While ENaC is critical for channel functionality,α,β , & γ ENaC maximize channel function. To date, there are four alternatively spliced forms of the subunit of ENaC ( ENaC-a, -b, -c, & -d) that have been published in rats, in addition to the major α ENaC transcript. While ENaC-a, -c & -d transcripts are low abundance transcripts compared to full-length α ENaC, ENaC-b is a higher abundance and salt-sensitive transcript compared to full-length ENaC. Presentation of the hypothesis. ENaC-b protein, which is preferentially produced in Dahl R rats, to a greater extent on high salt diet, exerts a dominant negative effect on full-length ENaC subunit by physically binding to and trapping full-length ENaC subunit in the endoplasmic reticulum, and finally accelerating full-length ENaC proteolytic degradation in a dose-dependent manner. Testing the hypothesis. 1) To examine the mRNA and protein abundance of ENaC-b relative to ENaC full-length in kidney, lung, and taste tissues of Dahl rats. 2) To compare the expression (mRNA and protein) of ENaC-b in kidneys of Dahl S and R rats on regular and high salt diet. 3) To examine the putative binding of ENaC-b proteins to full-length ENaC in vitro and to determine the impact of such binding on full-length ENaC expression in vitro. Implications of the hypothesis. Our studies will be the first to demonstrate the over-expression of salt-sensitive ENaC-b spliced form in kidney tissues of Dahl R rats at the expense of full-length ENaC. The current proposal will provide highly novel insights into the putative mechanisms leading to ENaC hypoactivity in high-salt-fed Dahl R rats. Finally, findings from the present proposal will uncover a new mechanism by which alternative splicing may control the regulation of ENaC expression/function. © 2010 Shehata; licensee BioMed Central Ltd.