Abstract
Epithelial Na+ channels facilitate the transport of Na+ across high resistance epithelia. Proteolytic cleavage has an important role in regulating the activity of these channels by increasing their open probability. Specific proteases have been shown to activate epithelial Na+ channels by cleaving channel subunits at defined sites within their extracellular domains. This minireview addresses the mechanisms by which proteases activate this channel and the question of why proteolysis has evolved as a mechanism of channel activation.
Highlights
Where Are ENaC Subunits Cleaved?Der suggested that proteases have a role in activating ENaC [3]. A series of studies over the past decade have confirmed that proteases activate ENaC and have begun to elucidate the mechanism by which this occurs
Epithelial Na؉ channels facilitate the transport of Na؉ across high resistance epithelia
This minireview addresses several questions regarding the role of ENaC subunit proteolysis in regulating channel gating. (i) Where are ENaC subunits cleaved? (ii) Which proteases mediate ENaC cleavage? (iii) Why are channels activated by proteolysis? (iv) Is proteolysis responsible, in part, for the highly variable channel Po that has been noted for ENaC? (v) Why have ENaCs evolved as channels that require proteolysis for activation?
Summary
Der suggested that proteases have a role in activating ENaC [3]. A series of studies over the past decade have confirmed that proteases activate ENaC and have begun to elucidate the mechanism by which this occurs. Relevant cleavage sites were identified within the proximal regions of the extracellular domains of the ␣ and ␥ subunits, as mutations of putative protease consensus cleavage sites prevented both subunit cleavage and channel activation (Fig. 1) [12,13,14]. Jasti et al [15] recently resolved the crystal structure of the acid-sensing ion channel ASIC1, a member of the ENaC/degenerin ion channel family. The extracellular domain of ASIC1 has a highly ordered structure that resembles an outstretched hand containing a ball and has defined subdomains termed wrist, finger, thumb, palm, -ball, and knuckle (Fig. 2) [15]. Sites of ENaC subunit proteolysis that have been shown to be functionally relevant are within the “finger” domains and are likely located at peripheral sites that would be expected to be accessible to proteases (Fig. 2). The finger domain of the  subunit lacks protease cleavage sites and instead exhibits three con-
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