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Sci. Signal., 14 October 2008
Vol. 1, Issue 41, p. ec359
[DOI: 10.1126/scisignal.141ec359]


Channels Inhibiting ENaC Activation

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Na+ movement across various transporting epithelia depends on its entry through apical epithelial Na+ channels (ENaC) and its exit by means of a basolateral Na+-K+-ATPase. ENaC activity is inhibited by extracellular and intracellular Na+, helping maintain Na+ homeostasis through negative feedback. Noting that ENaC is activated by proteolytic cleavage, and is present in both cleaved and uncleaved forms at the cell surface, Knight et al. investigated Na+’s effects on its proteolytic activation. When human embryonic kidney (HEK) 293T cells expressing the {alpha}, β, and {gamma} subunits of ENaC were incubated in medium containing 135 mM Na+, more of the cell surface {alpha}-subunit ({alpha}ENaC) was in the full-length than in the cleaved form, whereas this ratio was reversed in 0 mM Na+. The ratio of full-length to cleaved {alpha}ENaC increased as Na+ concentration was increased to 34 mM, but not thereafter. When Fischer rat thyroid cells expressing ENaC were used to create a barrier between compartments containing 135 mM Na+, the initial current sensitive to amiloride (an ENaC blocker) was greater in cells preincubated in 0 mM Na+ than in 135 mM Na+. Moreover, trypsin increased current in cells preincubated in 135 mM Na+ but had little effect on current in those preincubated in 0 mM Na+. A combination of pharmacological and mutational analysis indicated that proteolytic cleavage of ENaC was regulated by intracellular Na+. The 135 mM Na+ inhibited proteolysis of ENaC by trypsin without inhibiting trypsin’s enzymatic activity. The authors propose that increased intracellular Na+ inhibits ENaC activation through Na+-dependent regulation of cleavage site accessibility.

K. K. Knight, D. M. Wentzlaff, P. M. Snyder, Intracellular sodium regulates proteolytic activation of the epithelial sodium channel. J. Biol. Chem. 283, 27477-27482 (2008). [Abstract] [Full Text]

Citation: E. M. Adler, Inhibiting ENaC Activation. Sci. Signal. 1, ec359 (2008).

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