TY - JOUR T1 - Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits JF - bioRxiv DO - 10.1101/2021.02.25.432706 SP - 2021.02.25.432706 AU - Niklas Brake AU - Adamo S Mancino AU - Yuhao Yan AU - Takushi Shimomura AU - Heika Silveira AU - Yoshihiro Kubo AU - Anmar Khadra AU - Derek Bowie Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/25/2021.02.25.432706.abstract N2 - Voltage-gated sodium (Nav) channels mediate rapid millisecond electrical signaling in excitable cells. Auxiliary subunits, β1-β4, are thought to regulate Nav channel function through covalent and/or polar interactions with the channel’ s voltage-sensing domains. How these interactions translate into the diverse and variable regulatory effects of β-subunits remains unclear. Here, we find that the intrinsic movement order of the voltage-sensing domains during channel gating is unexpectedly variable across Nav channel isoforms. This movement order dictates the channel’ s propensity for closed-state inactivation, which in turn modulates the actions of β1 and β3. We show that the differential regulation of skeletal muscle, cardiac, and neuronal Nav channels is explained by their variable levels of closed-state inactivation. Together, this study provides a unified mechanism for the regulation of all Nav channel isoforms by β1 and β3, which explains how the fixed structural interactions of auxiliary subunits can paradoxically exert variable effects on channel function.Competing Interest StatementThe authors have declared no competing interest. ER -