Functional domains within the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels

Abstract

Application of recombinant DNA technology and electrophysiology to the study of amiloride-sensitive Na+ channels has resulted in an enormous increase in the understanding of the structure-function relationships of these channels. Moreover, this knowledge has permitted the elucidation of the physiological roles of these ion channels in cellular processes as diverse as transepithelial salt and water movement, taste perception, volume regulation, nociception, neuronal function, mechanosensation, and even defaecation. Although members of this ever-growing superfamily of ion channels (the Deg/ENaC superfamily) share little amino acid identity, they are all organized similarly, namely, two short N- and C-termini, two short membrane-spanning segments, and a very large extracellular loop domain. In this brief Topical Review, we discuss the structural features of each domain of this Deg/ENaC superfamily and, using ENaC as a model, show how each domain relates to overall channel function.

Figure 1. Major branches of the Deg/ENaC superfamily

Figure 2. Membrane topology of each subunit (α-, β- and γ-) ENaC

M1 and M2 indicate helical transmembrane domains; CRD1 and CRD2 indicate cysteine-rich domains; glycosylation sites are indicated (6 on α-ENaC, 12 on β-ENaC, and 5 on γ-ENaC). The filled bar within CRD1 of α-ENaC indicates the relative position of a 6 amino acid region known to bind amiloride (Kieber-Emmons et al. 1999).

Figure 3. Amino acid alignment of α(δ)-, β- and γ-ENaC in the N-terminal domain

Figure 4. Effect of amiloride on α_H282D-rENaC and α_H282Dβγ-rENaC in planar lipid bilayers

Experiments were performed in symmetrical 100 mM NaCl, 10 mM Mops (pH 7.4). Further experimental details can be found in Ismailov et al. (1997). Each point represents the mean of at least three separate experiments.

Figure 5. Amino acid alignment of α(δ)-, β- and γ-ENaC in the region of the second large hydrophobic domain (H2M2)

The domain between the vertical dotted lines is H2, and the region to the right of the second vertical dotted line is the M2 region (partial).