Abstract
Voltage-gated sodium (Nav) channels form the basis for the initiation of the action potential in excitable cells by allowing sodium ions to pass through the cell membrane. The Nav channel α subunit is known to function both with and without associated β subunits. There is increasing evidence that these β subunits have multiple roles that include not only influencing the voltage-dependent gating but also the ability to alter the spatial distribution of the pore-forming α subunit. Recent structural data has shown possible ways in which β1 subunits may interact with the α subunit. However, the position of the β1 subunit would not be compatible with a previous trimer structure of the β3 subunit. Furthermore, little is currently known about the dynamic behavior of the β subunits both as individual monomers and as higher order oligomers. Here, we use multiscale molecular dynamics simulations to assess the dynamics of the β3, and the closely related, β1 subunit. These findings reveal the spatio-temporal dynamics of β subunits and should provide a useful framework for interpreting future low-resolution experiments such as atomic force microscopy.
Highlights
The recent structures of the Nav α/β subunit complexes revealed the β1 Ig domain to adopt a conformation such that the long axis of the strands sits roughly parallel to the membrane surface
We investigated the dynamic behavior of full-length monomeric β1 and β3 in a POPC bilayer system using 25 replicas of 400 ns unbiased Molecular Dynamics (MD) simulations
We have explored the dynamics of the β1 and β3 subunit monomers with a lipid bilayer
Summary
Voltage-gated sodium (Nav) channels are the initiators of action potentials in electrically excitable cells and are implicated in many disease and pathological states including cardiac arrhythmia (Watanabe et al, 2008), epilepsy (Audenaert et al, 2003; van Gassen et al, 2009), neuropsychiatric disorders (Gargus, 2006), and chronic pain (Shah et al, 2000, 2001; Takahashi et al, 2003; Bouza and Isom, 2018). Β subunits function independently as cell-adhesion molecules (CAMs) (Isom et al, 1995; Rougon and Hobert, 2003; Yu et al, 2003) and may play a role in Nav channel clustering at the nodes of Ranvier (Ratcliffe et al, 2001) to promote the propagation of the action potential. The β1 subunit has been shown to stabilize the Nav 1.7 channel against mechanical
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