Regulation of ENaC by small G proteins

Abstract

Small G proteins are recognized to regulate diverse cellular processes. We have shown previously that the epithelial Na+ channel (ENaC) is regulated by Ras and Rho GTPases. K‐Ras, RhoA and Rac1 markedly increase activity of ENaC reconstituted in CHO cells in a GTP‐dependent manner. However, their transductionpathways and mechanisms of activation are different; K‐Ras increases channel open probability via PI3‐kinase signaling, whereas RhoA increase channel membrane levels. Regulation of ENaC open probability by PI3‐kinaseis a direct consequence of the physical association of the product of PI3‐kinase, PI(3,4,5)P3with the channel. RhoA activates ENaC via Rho‐kinase and subsequent activation of PI(4)P5‐kinase with concomitant increases in PI(4,5)P2 levels promoting channel insertion into the plasma membrane. Recent studies reveal that multiple Rab isoforms physically interact with and/or modulate the activity of several ion channels. Rab11a is well‐established as a participant in the regulation of recycling endosomal trafficking. Rab11a is associated with vesicles in the apical portion of epithelial cells near the centrosome and beneath the apical plasma membrane. Co‐expression of Rab11a with ENaC results in a significant increase in channel activity. We conclude that Rab11a may be important in the trafficking of ENaC.Supported by AHA.