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Address correspondence to Bernard C. Rossier, Institut de Pharmacologie et de Toxicologie, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland. Fax: (41) 21-692-5355; E-mail: Bernard.Rossier{at}ipharm.unil.ch
Sodium balance is maintained by the precise regulation of the activity of the epithelial sodium channel (ENaC) in the kidney. We have recently reported an extracellular activation of ENaC-mediated sodium transport (INa) by a GPI-anchored serine protease (mouse channel–activating protein, mCAP1) that was isolated from a cortical collecting duct cell line derived from mouse kidney. In the present study, we have identified two additional membrane-bound serine proteases (mCAP2 and mCAP3) that are expressed in the same cell line. We show that each of these proteases is able to increase INa 6–10-fold in the Xenopus oocyte expression system. INa and the number (N) of channels expressed at the cell surface (measured by binding of a FLAG monoclonal I125-radioiodinated antibody) were measured in the same oocyte. Using this assay, we show that mCAP1 increases INa 10-fold (P < 0.001) but N remained unchanged (P = 0.9), indicating that mCAP1 regulates ENaC activity by increasing its average open probability of the whole cell (wcPo). The serum- and glucocorticoid-regulated kinase (Sgk1) involved in the aldosterone-dependent signaling cascade enhances INa by 2.5-fold (P < 0.001) and N by 1.6-fold (P < 0.001), indicating a dual effect on N and wcPo. Compared with Sgk1 alone, coexpression of Sgk1 with mCAP1 leads to a ninefold increase in INa (P < 0.001) and 1.3-fold in N (P < 0.02). Similar results were observed for mCAP2 and mCAP3. The synergism between CAPs and Sgk1 on INa was always more than additive, indicating a true potentiation. The synergistic effect of the two activation pathways allows a large dynamic range for ENaC-mediated sodium regulation crucial for a tight control of sodium homeostasis.
Key Words: epithelial sodium channel • amiloride • serum glucocorticoid–regulated kinase 1 (Sgk1) • aldosterone • NEDD4
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