Allosteric inhibitors targeting the calmodulin-PIP2 interface of SK4 K⁺ channels for atrial fibrillation treatment.

ABSTRACT: The Ca²⁺-activated SK4 K⁺ channel is gated by Ca²⁺-calmodulin (CaM) and is expressed in immune cells, brain, and heart. A cryoelectron microscopy (cryo-EM) structure of the human SK4 K⁺ channel recently revealed four CaM molecules per channel tetramer, where the apo CaM C-lobe and the holo CaM N-lobe interact with the proximal carboxyl terminus and the linker S4-S5, respectively, to gate the channel. Here, we show that phosphatidylinositol 4-5 bisphosphate (PIP2) potently activates SK4 channels by docking to the boundary of the CaM-binding domain. An allosteric blocker, BA6b9, was designed to act to the CaM-PIP2-binding domain, a previously untargeted region of SK4 channels, at the interface of the proximal carboxyl terminus and the linker

SUBMITTER: Burg S 

PROVIDER: S-EPMC9407317 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature