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Am J Physiol Renal Physiol (January 21, 2003). doi:10.1152/ajprenal.00373.2002
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Submitted on October 16, 2002
Accepted on January 20, 2003

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

Rachell E. Booth1 and James D. Stockand1*

1 Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA

* To whom correspondence should be addressed. E-mail: stockand{at}uthscsa.edu.

Renal A6 epithelial cells were used to determine the mechanism by which PKC decreases ENaC activity. Activation of PKC reduced relative Na+ reabsorption to less than 20% within 60 minutes. This decrease was sustained over the next 24-48 hrs. In response to PKC signaling, {alpha}-, {beta}-, and {gamma}ENaC levels were 0.97, 0.36, and 0.39 after 24 hrs., respectively, with the levels of the latter two subunits being significantly decreased. The PKC-mediated decreases in {beta}- and {gamma}ENaC were significantly reversed by simultaneous addition of the MEK 1/2 inhibitors, U-0126 and PD-98059. These inhibitors, in addition, protected Na+ reabsorption from PKC demonstrating that the MAPK 1/2 cascade, in some instances, plays a central role in down-regulation of ENaC activity. The effects of PKC on {beta}- and {gamma}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 {gamma}ENaC was degraded within 1 hr. after treatment with inhibitors of synthesis; however, a significant pool was "protected" from inhibitors for up to 12 hrs. Protein kinase C affected this "protected" pool of {gamma}ENaC. Moreover, proteosome inhibitors (MG-132 and lactacystin) reversed PKC effects on this protected pool of {gamma}ENaC. Thus, PKC signaling via activating the MAPK 1/2 cascade in A6 cells promotes degradation of {gamma}ENaC.




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