1 The epithelial sodium channel δ subunit : new notes for an old song 2

20 Amiloride-sensitive epithelial Na channels (ENaC) can be formed by different combinations of 21 four homologous subunits, named α, β, γ and δ. In addition to providing an apical entry pathway for 22 transepithelial Na reabsorption in tight epithelia such as the kidney distal tubule and collecting duct, 23 ENaCs are also expressed in non-epithelial cells, where they may play different functional roles. 24 The δ subunit of ENaC was originally identified in humans and is able to form amiloride-sensitive 25 Na channels alone or in combination with β and γ, generally resembling the canonical kidney 26 ENaC formed by α, β and γ. However, δ differs from α in its tissue distribution and channel 27 properties. In spite of the low sequence conservation between α and δ (37% identity), their similar 28 functional characteristics provide an excellent model to explore structural correlates of specific 29 ENaC biophysical and pharmacological properties. Moreover, the study of cellular mechanisms 30 modulating the activity of different ENaC subunit combinations provides an opportunity to gain 31 insight into the regulation of the channel. In this review we examine the evolution of ENaC genes, 32 channel subunit composition, the distinct functional and pharmacological features that δ confers to 33 ENaC and how this can be exploited to better understand this ion channel. Finally, we briefly 34 consider possible functional roles of the δ ENaC subunit. 35 36 37