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An epithelial serine protease activates the amiloride-sensitive sodium channel

Nature volume 389, pages 607–610 (1997)Cite this article

Abstract

Sodium balance, and ultimately blood pressure and extracellular fluid volume, is maintained by precise regulation of the activity of the epithelial sodium channel (ENaC)1,2,3. In a Xenopus kidney epithelial cell line (A6), exposure of the apical membrane to theprotease inhibitor aprotinin reduces transepithelial sodium transport. Sodium-channel activity can be restored by subsequent exposure to the nonspecific protease trypsin. Using A6 cells and a functional complementation assay to detect increases in ENaC activity, we have cloned a 329-residue protein belonging to the serine protease family. We show that coexpression of this protein with ENaC in Xenopus oocytes increases the activity of the sodiumchannel by two- to threefold. This channel-activating protease (CAP1) is expressed in kidney, gut, lung, skin and ovary. Sequence analysis predicts that CAP1 is a secreted and/or glycosylphosphatidylinositol-anchored protein: ENaC activity would thus be regulated by the activity of a protease expressed at the surface of the same cell. This previously undiscovered mechanism for autocrine regulation may apply to other ion channels, in particular to members of the ENaC family that are present in neurons and epithelial cells.

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Figure 1: Effects of aprotinin and trypsin on sodium transport in A6 cells.
Figure 2: Comparison of the amino-acid sequence of Xenopus CAP1 with other serine proteases: human prostasin (1 to 363), human trypsin (1 to 247), human hepsin (114 to 417), human kallikrein (327 to 638) and human tissue-plasminogen activator (tPA) (208 to 562).
Figure 3: Northern blot analysis of CAP1 mRNA expression in Xenopus laevis tissues.
Figure 4: Functional effects of CAP1 expression on ENaC activity in Xenopus oocytes.

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Acknowledgements

We thank E. Hummler, K. Geering, M. Schapira and L. Schild for critically reading the manuscript. This work was supported by grants from the Swiss National Foundation for Scientific Research and Human Frontier Science Program; V.V. was supported by a fellowship from the European Molecular Biology Organization.

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  1. Institut de Pharmacologie et de Toxicologie de l'Universit, Rue du Bugnon 27, Lausanne, CH-1005, Switzerland

    Vronique Vallet, Ahmed Chraibi, Hans-Peter Gaeggeler, Jean-Daniel Horisberger & Bernard C. Rossier

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  1. Vronique Vallet
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Correspondence to Bernard C. Rossier.

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Vallet, V., Chraibi, A., Gaeggeler, HP. et al. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 389, 607–610 (1997). https://doi.org/10.1038/39329

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