Structural Insights into Subunit-Dependent Functional Regulation in Epithelial Sodium Channels

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Epithelial sodium channels (ENaC) are critical for sodium reabsorption in mammals.
• Four subunits (α, β, γ, δ) are known, forming various heteromeric complexes.
• The structure of the αβγ ENaC complex is known, but others remain uncharacterized.

Purpose of the Study:

• To elucidate the structures of ENaC complexes with varying subunit compositions.
• To understand how different subunits contribute to ENaC channel properties.
• To define the structural basis for functional differences between ENaC variants.

Main Methods:

• Co-expression of human δ, β, and γ ENaC subunits.
• Single-particle cryo-electron microscopy (cryo-EM) for structural determination.
• Analysis of distinct ENaC complex structures.

Main Results:

• Three distinct ENaC complexes were identified.
• Conserved β and γ subunit positions were observed across complexes.
• The α subunit position was occupied by either δ or a second β subunit.
• The δ subunit induced structural changes in the γ subunit, altering channel activity.

Conclusions:

• ENaC subunit composition dictates channel structure and function.
• The δ subunit's presence modifies ENaC structure, explaining functional variations.
• These findings provide a mechanism for how ENaC subunit diversity tunes channel activity.