Ligand activation mechanisms of human KCNQ2 channel.

ABSTRACT: The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP₂), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP₂, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms

SUBMITTER: Ma D 

PROVIDER: S-EPMC10587151 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature