title: Physiologic regulation of the epithelial sodium channel by phosphatidylinositides.
abstract: OBJECTIVE
  Epithelial sodium channel (ENaC) activity is limiting for sodium reabsorption in the distal nephron. Humans regulate blood pressure by fine-tuning sodium balance through control of ENaC. ENaC dysfunction causes some hypertensive and renal salt wasting diseases. Thus, it is critical to understand the cellular mechanisms controlling ENaC activity.
  
  
  RESULTS
  ENaC is sensitive to phosphatidylinositol 4,5-bisphosphate (PIP2), the target of phospholipase C-mediated metabolism, and phosphatidylinositiol 3,4,5-trisphosphate (PIP3), the product of phosphatidylinositide 3-OH kinase (PI3-K). PIP2 is permissive for ENaC gating possibly interacting directly with the channel. Activation of distal nephron P2Y receptors tempers ENaC activity by promoting PIP2 metabolism. This is important because gene deletion of P2Y2 receptors causes hypertension associated with hyperactive ENaC. Aldosterone, the final hormone in a negative-feedback cascade activated by decreases in blood pressure, increases ENaC activity. PIP3 sits at a critical bifurcation in the aldosterone-signaling cascade, increasing ENaC open probability and number. PIP3-effectors mediate increases in ENaC number by suppressing channel retrieval. PIP3 binds ENaC, at a site distinct from that important to PIP2 regulation, to modulate directly open probability.
  
  
  CONCLUSIONS
  Phosphoinositides play key roles in physiologic control of ENaC and perhaps dysregulation plays a role in disease associated with abnormal renal sodium handling.
authors.affiliation: University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
authors.forename: Oleh
authors.initials: O
authors.lastname: Pochynyuk
authors.forename: Vladislav
authors.initials: V
authors.lastname: Bugaj
authors.forename: James D
authors.initials: JD
authors.lastname: Stockand
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels / Q000502:physiology*; D006801:Humans; D010716:Phosphatidylinositols / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D053503:Epithelial Sodium Channels; D010716:Phosphatidylinositols