Targeted degradation of ENaC in response to PKC activation of the ERK1/2 cascade

Rachell E. Booth, James D Stockand

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Renal A6 epithelial cells were used to determine the mechanism by which protein kinase C (PKC) decreases epithelial Na+ channel (ENaC) activity. Activation of PKC reduced relative Na+ reabsorption to <20% within 60 min. This decrease was sustained over the next 24-48 h. In response to PKC signaling, α-, β-, and γ-ENaC levels were 0.97, 0.36, and 0.39, respectively, after 24 h, with the levels of the latter two subunits being significantly decreased. The PKC-mediated decreases in β- and γ-ENaC were significantly reversed by simultaneous addition of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-1/2 inhibitors U-0126 and PD-98059. These inhibitors, in addition, protected Na+ reabsorption from PKC, demonstrating that the MAPK1/2 cascade, in some instances, plays a central role in downregulation of ENaC activity. The effects of PKC on β- and γ-ENaC levels were additive with those of inhibitors of transcription (actinomycin D) and translation (emetine and cycloheximide), suggesting that PKC promotes subunit degradation and does not affect subunit synthesis. The bulk of whole cell γ-ENaC was degraded within 1 h after treatment with inhibitors of synthesis; however, a significant pool was "protected" from inhibitors for up to 12 h. PKC affected this protected pool of γ-ENaC. Moreover, proteosome inhibitors (MG-132 and lactacystin) reversed PKC effects on this protected pool of γ-ENaC. Thus PKC signaling via MAPK1/2 cascade activation in A6 cells promotes degradation of γ-ENaC.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume284
Issue number5 53-5
StatePublished - May 1 2003

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Epithelial Sodium Channels
Protein Kinase C
Emetine
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Dactinomycin
Cycloheximide
Mitogen-Activated Protein Kinases
Down-Regulation
Epithelial Cells

Keywords

  • Hypertension
  • Lactacystin
  • MG-132
  • MG-262
  • Proteosome
  • Sodium transport

ASJC Scopus subject areas

  • Physiology

Cite this

Targeted degradation of ENaC in response to PKC activation of the ERK1/2 cascade. / Booth, Rachell E.; Stockand, James D.

In: American Journal of Physiology - Renal Physiology, Vol. 284, No. 5 53-5, 01.05.2003.

Research output: Contribution to journalArticle

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