Journal article

Progesterone down-regulates the open probability of the amiloride-sensitive epithelial sodium channel via a Nedd4-2-dependent mechanism

  • Michlig, Stéphanie Département de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland
  • Harris, Michael Département de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland
  • Loffing, Johannes Département de Médicine, Unité d'Anatomie, Université de Fribourg, Switzerland
  • Rossier, Bernard C. Département de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland
  • Firsov, Dmitri Département de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland
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    19.09.2005
Published in:
  • Journal of Biological Chemistry. - 2005, vol. 280, no. 46, p. 38264-38270
English Activation of the mitogen-activated protein (MAP) kinase cascade by progesterone in Xenopus oocytes leads to a marked down-regulation of activity of the amiloride-sensitive epithelial sodium channel (ENaC). Here we have studied the signaling pathways involved in progesterone effect on ENaC activity. We demonstrate that: (i) the truncation of the C termini of the αβγENaC subunits results in the loss of the progesterone effect on ENaC; (ii) the effect of progesterone was also suppressed by mutating conserved tyrosine residues in the Pro-X-X-Tyr (PY) motif of the C termini of the βand γ ENaC subunits (βY618A and γY628A); (iii) the down-regulation of ENaC activity by progesterone was also suppressed by co-expression ENaC subunits with a catalytically inactive mutant of Nedd4-2, a ubiquitin ligase that has been previously demonstrated to decrease ENaC cell-surface expression via a ubiquitin-dependent internalization/degradation mechanism; (iv) the effect of progesterone was significantly reduced by suppression of consensus sites (βT613A and γT623A) for ENaC phosphorylation by the extracellular-regulated kinase (ERK), a MAP kinase previously shown to facilitate the binding of Nedd4 ubiquitin ligases to ENaC; (v) the quantification of cell-surface-expressed ENaC subunits revealed that progesterone decreases ENaC open probability (whole cell Po, wcP o) and not its cell-surface expression. Collectively, these results demonstrate that the binding of active Nedd4-2 to ENaC is a crucial step in the mechanism of ENaC inhibition by progesterone. Upon activation of ERK, the effect of Nedd4-2 on ENaC open probability can become more important than its effect on ENaC cell-surface expression.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/299883
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