The second transmembrane domain of the large conductance, voltage- and calcium-gated potassium channel beta(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 beta(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 beta(1) to mediate LC action; beta(1) and a simple phospholipid microenvironment suffice. Since beta(1) senses LC but beta(4) does not, we made chimeras swapping regions between these subunits and, following channel heterologous expression, demonstrate that beta(1) TM2 is a bile acid-recognizing sensor.
Bukiya
Anna N
AN
Department of Pharmacology, University of Tennessee HSC, Memphis, TN 38163, USA.
Vaithianathan
Thirumalini
T
Toro
Ligia
L
Dopico
Alejandro M
AM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000737:chemistry* / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism; D008095:Lithocholic Acid / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D014981:Xenopus
D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D008051:Lipid Bilayers; D008095:Lithocholic Acid; D002118:Calcium