Bile acids regulate the epithelial Na⁺ channel in native tissues through direct binding at multiple sites

Area of Science:

• Physiology
• Molecular Biology
• Biochemistry

Background:

• Bile acids, traditionally known for lipid emulsification, are recognized as signaling molecules regulating physiological processes.
• The epithelial sodium channel (ENaC) plays critical roles in fluid balance and is implicated in various physiological and pathophysiological conditions.
• Previous studies indicated bile acid regulation of ENaC in vitro, but in vivo mechanisms remained unclear.

Purpose of the Study:

• To investigate whether bile acids regulate ENaC in native tissues.
• To determine if bile acids directly bind to ENaC.
• To elucidate the specific subunits and mechanisms involved in bile acid-mediated ENaC regulation.

Main Methods:

• Investigated bile acid regulation of ENaC in mouse cortical collecting duct and colon.
• Employed photoaffinity labeling to detect direct binding of bile acids to ENaC subunits.
• Utilized Xenopus oocyte expression systems to functionally assess ENaC activity with varying subunits.

Main Results:

• Taurocholic acid and taurohyodeoxycholic acid were found to regulate ENaC in native mouse tissues.
• Photoaffinity labeling confirmed specific binding of bile acids to the β and γ ENaC subunits.
• Functional studies demonstrated that the α subunit alone was sufficient for taurocholic acid regulation, which was voltage-sensitive.

Conclusions:

• Bile acids directly bind to and regulate ENaC in native tissues by modulating channel open probability.
• Binding occurs at multiple sites, including the β and γ subunits, with potential interaction near pore-forming helices.
• These findings establish bile acids as significant ENaC regulatory effectors with implications for systemic physiology and disease.