Effects of electric-field reshaping on voltage sensing in voltage-gated sodium channels.

Abstract

Voltage-gated sodium channels (Navs) are responsible for the depolarizing phase of the action potential with essential roles in fast electrical signalling. Membrane depolarization triggers opening of Nav channels via activation of their voltage-sensing domains (VSD). The electric field across the membrane acts on a series of positively charged residues and induces their transmembrane relocation, which in turn triggers conformational changes that eventually lead to the opening of the sodium-conducting pore. Voltage dependence of the activation process can be described in terms of the gating charge that links energetics of VSD activation to the transmembrane voltage. Notably, the gating charge is defined by coupling of charged residues to the external electric field, whose shape is therefore crucial for Nav activation. Here, we employed molecular dynamics simulations of cardiac Nav1.5 and bacterial NavAb to gain atomic-level insights into the voltage-sensing mechanisms of Navs. Using our recently developed tool g_elpot to quantify VSD electrostatics with high spatial resolution, we found that, in contrast to earlier low-resolution studies, the electric field within VSDs of Nav channels has a complex isoform- and domain-specific shape, which prominently depends on the activation state of a VSD. Due to this field reshaping, not only translocated basic but also relatively static acidic residues contribute significantly to the gating charge. In the case of NavAb, we found that the transition between the resolved activated- and resting-state structures results in the gating charge of 8e, which is noticeably lower than experimental values of 12-16e. Our analysis of VSD electrostatics thus indicates that the resting-state structure represents an intermediate state of channel activation. In conclusion, our results provide an atomic-level description of the gating charge in Nav channels, and reveal the importance of electric-field reshaping for the energetics of voltage gating.