The second transmembrane domain of the large conductance, voltage‐ and calcium‐gated potassium channel β 1 subunit is a lithocholate sensor

Bile acids and other steroids modify large conductance, calcium‐ and voltage‐gated potassium (BK) channel activity contributing to non‐genomic modulation of myogenic tone. Accessory BK β 1 subunits are necessary for lithocholate (LC) to activate BK channels and vasodilate. The protein regions that sense steroid action, however, remain unknown. Using recombinant channels in 1‐palmitoyl‐2‐oleoyl‐phosphatidylethanolamine/1‐palmitoyl‐2‐oleoyl‐phosphatidylserine bilayers we now demonstrate that complex proteolipid domains and cytoarchitecture are unnecessary for β 1 to mediate LC action; β 1 and a simple phospholipid microenvironment suffice. Since β 1 senses LC but β 4 does not, we made chimeras swapping regions between these subunits and, following channel heterologous expression, demonstrate that β 1 TM2 is a bile acid‐recognizing sensor.