Regulation and dysregulation of epithelial Na+ channels

Abstract

Epithelial Na(+) channels (ENaC) form a highly regulated pathway for the reabsorption of Na(+) from urine. This regulation can take place at a number of different levels, including synthesis of channel protein, trafficking of the protein between the surface and internal membranes, proteolytic cleavage and channel gating. This article reviews the role of these different modes of regulation under physiological conditions and considers the possible contributions of dysregulation of these processes in disease states, particularly hypertension.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+ Channel

“…4, D and E). During its short lifetime at the cell surface, the channel evolves between different gating modes of high and low open probability before its internalization (Garty and Palmer, 1997;Shimkets et al, 1997;Kleyman et al, 2001;Palmer et al, 2012).…”

Piece treaties connect ENaC subunits

“…1), and showed that the extent of cleavage correlated with the upregulation of the channels in vivo by the mineralocorticoid aldosterone. 3 This finding underscores the likely physiological relevance of proteolytic activation. However the reason for having such a step remains obscure.…”

Status of Fluid and Electrolyte Absorption in Cystic Fibrosis

“…ENaC trafficking to and from the apical membrane involves regulated processes that determine the density of ENaC in the apical membrane (Palmer et al 2012). Liddle's disease of inherited amiloride-sensitive hypertension is caused by mutations in the carboxy-terminal cytosolic tails of b-and g-ENaC, which contain highly conserved PY protein interaction motifs that mediate the association of ENaC with the E3 ubiquitin ligase, Nedd4-L (Schild et al 1996;Staub et al 2000).…”

“…Numerous signaling pathways, including SGK1, PKA, and MAP kinases, adjust the strength of the ENaC -Nedd4-L association through the phosphorylation status of specific residues, giving rise to wide tissue variability in the impact of this regulatory axis (Debonnevilles et al 2001). For example, the hypertension of patients with Liddle's disease is attributed to excess ENaC at the apical membrane of renal tubules (Palmer et al 2012). However, Liddle's disease patients show no evidence of increased Na þ absorption in respiratory epithelia (Knowles and Boucher 2002), suggesting that other mechanisms exist for controlling Na þ conductance in certain tissues.…”