The scaffold protein IQGAP1 regulates the epithelial Na⁺ channel

The epithelial Na⁺ channel (ENaC), by mediating the flow of Na⁺ ions across biological membranes, plays a key role in the regulation of Na⁺ and water absorption in several human epithelia. IQGAP1 is a scaffold protein that mediates diverse cellular processes, including intracellular signaling and trafficking. In this study, we establish that IQGAP1 binds to ENaC and regulates its functions. We observed that IQGAP1 coresides with aquaporin 2 in ENaC-expressing principal cells of the distal nephron of mouse kidney. We showed that purified IQGAP1 pulls down the α-, β-, and γ-subunits of ENaC. We demonstrated that endogenous IQGAP1 coimmunoprecipitates with ENaC subunits in Madin-Darby canine kidney cell lysates. Functionally, coexpression of IQGAP1 with ENaC in Xenopus oocytes reduces ENaC surface abundance and amiloride-sensitive Na⁺ transport activity. Together, our data indicate that IQGAP1 binds to ENaC, which likely influences channel trafficking to regulate its cell surface abundance and Na⁺ transport function. More broadly, these observations suggest new physiological roles for IQGAP1 in Na⁺ and water absorption in epithelium.