Cassell, Samantha, Li, Weiyan, Krautwald, Simon, Khoshouei, Maryam, Lee, Tony, Hou, Joyce, Guan, Wendy, Peukert, Stefan, Weihofen, Wilhelm and Whicher, Jonathan (2025) Mechanism of SK2 channel gating and its modulation by the bee toxin apamin and small molecules. eLife, 14. ISSN 2050-084X

Abstract

Small-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in development for the treatment of neurological and cardiovascular diseases, though the mechanisms of pharmacological modulation remain incompletely understood. We determined structures of an SK2-4 chimeric channel in Ca2+-bound and Ca2+-free conformations and in complex with the bee toxin apamin, a small molecule inhibitor, and a small molecule activator. The structures revealed that the S3-S4 linker forms a hydrophobic constriction at the extracellular opening of the pore. Apamin binds to this extracellular constriction and blocks the exit of potassium ions. Furthermore, we identified a structurally related SK2 inhibitor and activator that bind to the transmembrane domains. The compounds exert opposing effects on gating by differentially modulating the conformation of the S6 helices. These results provide important mechanistic insights to facilitate the development of targeted SK2 channel therapeutics.

Item Type:	Article
Keywords:	Apamin Small-Conductance Calcium-Activated Potassium Channels Ion Channel Gating Humans Models, Molecular Calcium Protein Conformation Animals Bee Venoms Protein Binding
Date Deposited:	24 Dec 2025 00:45
Last Modified:	24 Dec 2025 00:45
URI:	https://oak.novartis.com/id/eprint/56690