Abstract

The accessory beta 1 subunit modulates the Ca2+- and voltage-activated K+ (BK) channel gating properties mainly by increasing its apparent Ca2+ sensitivity. beta 1 plays an important role in the modulation of arterial tone and blood pressure by vascular smooth muscle cells (SMCs). 17 beta-estradiol (E2) increases the BK channel open probability (P-o) in SMCs, through a beta 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 beta 1 subunit, including the residues W163 and F166, as the binding site for E2. We further show that the increase in P-o 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 beta 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.