The second transmembrane domain of the large conductance, voltage‐ and calcium‐gated potassium channelβ1subunit is a lithocholate sensor

Abstract
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 BKβ1subunits 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 forβ1to mediate LC action;β1and a simple phospholipid microenvironment suffice. Sinceβ1senses LC butβ4does not, we made chimeras swapping regions between these subunits and, following channel heterologous expression, demonstrate thatβ1TM2 is a bile acid‐recognizing sensor.