The molecular nature of the 17?-Estradiol binding site in the voltage- and Ca2+-activated K+ (BK) channel ?1 subunit.

ABSTRACT: The accessory ?1 subunit modulates the Ca2+- and voltage-activated K+ (BK) channel gating properties mainly by increasing its apparent Ca2+ sensitivity. ?1 plays an important role in the modulation of arterial tone and blood pressure by vascular smooth muscle cells (SMCs). 17?-estradiol (E2) increases the BK channel open probability (Po) in SMCs, through a ?1 subunit-dependent modulatory effect. Here, using molecular modeling, bioinformatics, mutagenesis, and electrophysiology, we identify a cluster of hydrophobic residues in the second transmembrane domain of the ?1 subunit, including the residues W163 and F166, as the binding site for E2. We further show that the increase in Po induced by E2 is associated with a stabilization of the voltage sensor in its active configuration and an increase in the coupling between the voltage sensor activation and pore opening. Since ?1 is a key molecular player in vasoregulation, the findings reported here are of importance in the design of novel drugs able to modulate BK channels.

SUBMITTER: Granados ST 

PROVIDER: S-EPMC6620312 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature