Liddle-Mutation of the β-Subunit, but not the γ-Subunit, Attenuates Protein Kinase C-Mediated Inhibition of Human Epithelial Sodium Channels (hENaC)

Liddle-Mutation of the β-Subunit, but not the γ-Subunit, Attenuates Protein Kinase C-Mediated... Mammalian distal nephron and distal colon, prime sites for Na+ homeostasis, contain amiloride-sensitive epithelial sodium channels (ENaC). Protein kinase C (PKC) inhibits ENaC by phosphorylating serine and threonine residues within COOH termini of the β- and/or γ-subunits. Although some of these phosphorylation sites are close to the PY motifs, it is unclear whether they remain susceptible to PKC in Liddle-mutated ENaC β- and/or γ-subunits, where PY motifs are truncated, resulting in increased apical ENaC expression. We therefore studied the effects of PKC in wild-type and Liddle-mutated human epithelial Na+ channels (hENaC) expressed in Xenopus oocytes, using the dual-electrode voltage clamp technique. PKC activation using 500 nmol/l phorbol 12-myristate 13-acetate (PMA) decreased amiloride-sensitive Na+ currents by 80 % in oocytes expressing wild-type hENaC, an effect largely prevented by co-exposure to 50 µmol/l calphostin C (a specific inhibitor of PKC), whereas 500 nmol/l phorbol didecanoate (PDD), an inactive phorbol ester which does not stimulate PKC, had no effect. In oocytes expressing hENaC containing the Liddle-mutated β-subunit, PMA elicited a 54 % decrease in amiloride-sensitive Na+ currents, significantly (P < 0.0025) less than that in oocytes expressing wild-type hENaC. By contrast, in oocytes expressing hENaC containing the Liddle-mutated γ-subunit, PMA elicited a 68 % decrease in amiloride-sensitive Na+ current, similar (P = 0.10) to that in oocytes expressing wild-type hENaC. We conclude that hENaC incorporating the Liddle-mutated β-subunit lacks one or more PKC phosphorylation sites, thereby significantly reducing the inhibitory effect of PKC on Na+ channel activity, whereas hENaC incorporating Liddle-mutated γ-subunits remains as susceptible to PKC as wild-type hENaC. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

Liddle-Mutation of the β-Subunit, but not the γ-Subunit, Attenuates Protein Kinase C-Mediated Inhibition of Human Epithelial Sodium Channels (hENaC)

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/lp/springer_journal/liddle-mutation-of-the-subunit-but-not-the-subunit-attenuates-protein-brPyRQTfCD
Publisher
Springer US
Copyright
Copyright © 2016 by The Author(s)
Subject
Life Sciences; Biochemistry, general; Human Physiology
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s00232-015-9866-x
Publisher site
See Article on Publisher Site

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