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

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.