Referenced in: none

Automatically associated channels: Slo1

Title: Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment.

Authors: Timothy I Webb, Aravind Singh Kshatri, Roddy J Large, Adebola Morayo Akande, Subhrangsu Roy, Gerard P Sergeant, Noel G McHale, Keith D Thornbury, Mark A Hollywood

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2015 Feb 17 , 112, 2064-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25653338

Abstract
GoSlo-SR-5-6 is a novel large-conductance Ca(2+)-activated K(+) (BK) channel agonist that shifts the activation V1/2 of these channels in excess of -100 mV when applied at a concentration of 10 μM. Although the structure-activity relationship of this family of molecules has been established, little is known about how they open BK channels. To help address this, we used a combination of electrophysiology, mutagenesis, and mathematical modeling to investigate the molecular mechanisms underlying the effect of GoSlo-SR-5-6. Our data demonstrate that the effects of this agonist are practically abolished when three point mutations are made: L227A in the S4/S5 linker in combination with S317R and I326A in the S6C region. Our data suggest that GoSlo-SR-5-6 interacts with the transmembrane domain of the channel to enhance pore opening. The Horrigan-Aldrich model suggests that GoSlo-SR-5-6 works by stabilizing the open conformation of the channel and the activated state of the voltage sensors, yet decouples the voltage sensors from the pore gate.