The second transmembrane domain of the large conductance, voltage- and calcium-gated potassium channel β1 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 β1 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 β1 to mediate LC action; β1 and a simple phospholipid microenvironment suffice. Since β1 senses LC but β4 does not, we made chimeras swapping regions between these subunits and, following channel heterologous expression, demonstrate that β1 TM2 is a bile acid-recognizing sensor.