N-type fast inactivation of a eukaryotic voltage-gated sodium channel

• DOI: 10.1038/s41467-022-30400-w
• Publication Date: 2022-05-17T10:09:46Z
• Authors: Jiangtao Zhang; Yiqiang Shi; Junping Fan; Huiwen Chen; Zhanyi Xia; Bo Huang; Juquan Jiang; Jianke Gong; Zhuo Huang; Daohua Jiang
• Keywords: 0301 basic medicine; Cell biology; Science; Memristive Devices for Neuromorphic Computing; Voltage-gated ion channel; Biophysics; Action Potentials; Organic chemistry; Voltage-Gated Sodium Channels; Emiliania huxleyi; Helix (gastropod); Biochemistry; Article; Cellular and Molecular Neuroscience; 03 medical and health sciences; Engineering; Biochemistry, Genetics and Molecular Biology; FOS: Electrical engineering, electronic engineering, information engineering; Humans; Electrical and Electronic Engineering; Molecular Biology; Biology; Ecology; Voltage-Gated Channels; Sodium channel; Q; Cryoelectron Microscopy; Sodium; Eukaryota; Life Sciences; Neural Interface Technology; Allosteric regulation; Molecular Mechanisms of Ion Channels Regulation; Chemistry; Snail; FOS: Biological sciences; Physical Sciences; Phytoplankton; Ion channel; Gating; Neuroscience; Receptor; Nutrient

AbstractVoltage-gated sodium (NaV) channels initiate action potentials. Fast inactivation of NaV channels, mediated by an Ile-Phe-Met motif, is crucial for preventing hyperexcitability and regulating firing frequency. Here we present cryo-electron microscopy structure of NaVEh from the coccolithophore Emiliania huxleyi, which reveals an unexpected molecular gating mechanism for NaV channel fast inactivation independent of the Ile-Phe-Met motif. An N-terminal helix of NaVEh plugs into the open activation gate and blocks it. The binding pose of the helix is stabilized by multiple electrostatic interactions. Deletion of the helix or mutations blocking the electrostatic interactions completely abolished the fast inactivation. These strong interactions enable rapid inactivation, but also delay recovery from fast inactivation, which is ~160-fold slower than human NaV channels. Together, our results provide mechanistic insights into fast inactivation of NaVEh that fundamentally differs from the conventional local allosteric inhibition, revealing both surprising structural diversity and functional conservation of ion channel inactivation.