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The highly selective amiloride-sensitive epithelial sodium channel is expressed in the distal part of the nephron, the distal colon, and the lung. It plays a critical role in the control of sodium balance, extracellular volume, blood pressure, and of fluid reabsorption in the lung. The primary structure of the rat epithelial sodium channel has recently been determined. It is a heteromultimeric protein made up of three homologous subunits (α, β, and γ ). The biophysical properties, the cell distribution, and the regulation of this channel will be reviewed, with emphasis on its expression in the kidney, colon, and lung, where the clinical implications are most relevant. The epithelial sodium channel is a member of a novel gene superfamily that encodes cation channels involved in the control of cellular and extracellular volume and in the control of distinct functions such as taste transduction and mechanotransduction.