Regulation of the epithelial Na⁺ channel (ENaC) by phosphatidylinositides

Abstract

The epithelial Na ϩ channel (ENaC) is an endeffector of diverse cellular signaling cascades, including those with phosphatidylinositide second messengers. Recent evidence also suggests that in some instances, phospatidylinositides can directly interact with ENaC to increase channel activity by increasing channel open probability and/or membrane localization. We review here findings relevant to regulation of ENaC by phosphatidylinositol 4,5-bisphosphate (PIP 2) and phosphatidylinositol 3,4,5-triphosphate (PIP3). Similar to its actions on other ion channels, PIP2 is permissive for ENaC openings having a direct effect on gating. The PIP2 binding site in ENaC involved in this regulation is most likely localized to the NH 2 terminus of ␤-ENaC. PIP3 also affects ENaC gating but, rather than being permissive, augments open probability. The PIP3 binding site in ENaC involved in this regulation is localized to the proximal region of the COOH terminus of ␥-ENaC just following the second transmembrane domain. In complementary pathways, PIP 3 also impacts ENaC membrane levels through both direct actions on the channel and via a signaling cascade involving phosphoinositide 3-OH kinase (PI3-K) and the aldosterone-induced gene product serum and glucocorticoid-inducible kinase. The putative PIP 3 binding site in ENaC involved in direct regulation of channel membrane levels has not yet been identified. phosphatidylinositol 4,5-bisphosphate; phosphatidylinositol 3,4,5-triphosphate; receptor tyrosine kinase; insulin G protein-coupled receptor ION CHANNELS PLAY CRITICAL roles in every aspect of physiology. Moreover, ion channels have long been recognized to be important end-effectors of diverse cellular signaling cascades, including those having phosphatidylinositide second messengers. Direct regulation of ion channel activity by phosphatidylinositide-signaling molecules, in addition, is now becoming widely appreciated (reviewed in Ref. 33). This mechanism for ion channel modulation is recognized to be physiologically important, for its disruption, in some instances, leads to disease (e.g., Bartter's and Andersen's syndromes) (16,43,56,65). Diverse types of ion channels are directly modulated by phosphatidylinositides (3,17,42,58,74,84,96,97). Phosphatidylinositides, such as phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and phosphatidylinositol 3,4,5-triphosphate (PIP 3 ), directly interact with these channels to modulate gating (58,93,97). Several recent studies identify the epithelial Na ϩ channel (ENaC) as being a channel sensitive to direct phosphatidylinositide regulation.ENaC is a heteromeric channel composed of three distinct but similar subunits: ␣, ␤, and ␥ (8, 9). All ENaC subunits have NH 2 -and COOH-terminal cytosolic domains separated by two transmembrane domains and a large extracellular region. ENaC serves an essential physiological function, for its activity is limiting for Na ϩ absorption across many epithelia, including that in the distal renal nephron (reviewed in Refs. 27, 37, and 69). Thus ENaC is well positio...

Hydrogen Peroxide Stimulates the Epithelial Sodium Channel through a Phosphatidylinositide 3-Kinase-dependent Pathway

“…These studies indicate that ROS may stimulate PI3K and consequently promote the synthesis of PI(3,4,5)P 3 . We (18 -20) and others (21,22) have previously shown that PI(3,4,5)P 3 stimulates ENaC. Taken together, these studies suggest that H 2 O 2 may stimulate ENaC by elevating PI(3,4,5)P 3 through activation of PI3K.…”

Specific Palmitoyltransferases Associate with and Activate the Epithelial Sodium Channel

“…These include extracellular cations (H ϩ , Na ϩ , and other metals), anions (Cl Ϫ ), laminar shear stress, and proteases that cleave ENaC subunits at specific sites and release embedded inhibitory tracts (1, 2, 9 -14). Intracellular phosphorylation, inositol phospholipids, and cytoplasmic Cys palmitoylation also regulate ENaC P o (15)(16)(17)(18)(19)(20)(21).…”

Mechanisms of ENaC Regulation and Clinical Implications

“…115,116 Interestingly, phosphatidylinositol 3-kinase influences both ENaC trafficking (through SGK1 and/or Akt) and P o . 117 These myriad signaling pathways demonstrate a complex regulatory network that directly and indirectly influences ENaC surface expression and P o . Such mechanisms are likely operative in acute, subacute, and chronic changes in ENaC regulation.…”