The bile acid-sensitive ion channel is gated by Ca2+-dependent conformational changes in the transmembrane domain

TL;DR

The study reveals how calcium ions control the function of the bile acid-sensitive ion channel through structural changes.

Contribution

The paper provides the first structural and functional insights into Ca2+ modulation of the BASIC ion channel.

Findings

Cryo-EM structures show Ca2+ induces conformational changes in the transmembrane domain of BASIC.

A glutamate residue in the pore's extracellular vestibule is critical for Ca2+ binding and channel gating.

Calcium modulates BASIC through conformational changes rather than pore blockage.

Abstract

The bile acid-sensitive ion channel (BASIC) is the least understood member of the mammalian epithelial Na+ channel/degenerin (ENaC/DEG) superfamily of ion channels, which are involved in a variety of physiological processes. While some members of this superfamily, including BASIC, are inhibited by extracellular Ca2+ (Ca2+o), the molecular mechanism underlying Ca2+ modulation remains unclear. Here, by determining the structure of human BASIC (hBASIC) in the presence and absence of Ca2+ using single-particle cryo-electron microscopy (cryo-EM), we reveal Ca2+-dependent conformational changes in the transmembrane domain and β-linkers. Electrophysiological experiments further show that a glutamate residue in the extracellular vestibule of the pore underpins the Ca2+-binding site, whose occupancy determines the conformation of the pore and therefore ion flow through the channel. These results reveal the molecular principles governing gating of BASIC and its regulation by Ca2+ ions, demonstrating that Ca2+ ions modulate BASIC function via changes in protein conformation rather than solely from a pore-block, as proposed for other members of this superfamily.

The bile acid-sensitive ion channel (BASIC) is inhibited by extracellular Ca2+ . Here, authors present cryo-EM structure of human BASIC in the presence and absence of Ca2+ , providing insight into the Ca2+-dependent mechanism of the channel.

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