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| Home > Publications database > Domain- and state-specific shape of the electric field tunes voltage sensing in voltage-gated sodium channels |
| Typ | Amount | VAT | Currency | Share | Status | Cost centre |
| Page charges | 1700.51 | 0.00 | EUR | 100.00 % | (Zahlung erfolgt) | 44500 |
| Sum | 1700.51 | 0.00 | EUR | |||
| Total | 1700.51 |
| Journal Article | FZJ-2023-02226 |
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2023
Soc.
Bethesda, Md.
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Please use a persistent id in citations: doi:10.1016/j.bpj.2023.04.013 doi:10.34734/FZJ-2023-02226
Abstract: The ability to sense transmembrane voltage underlies most physiological roles of voltage-gated sodium (Nav) channels. Whereas the key role of their voltage-sensing domains (VSDs) in channel activation is well established, the molecular underpinnings of voltage coupling remain incompletely understood. Voltage-dependent energetics of the activation process can be described in terms of the gating charge that is defined by coupling of charged residues to the external electric field. The shape of the electric field within VSDs is therefore crucial for the activation of voltage-gated ion channels. Here, we employed molecular dynamics simulations of cardiac Nav1.5 and bacterial NavAb, together with our recently developed tool g_elpot, to gain insights into the voltage-sensing mechanisms of Nav channels via high-resolution quantification of VSD electrostatics. In contrast to earlier low-resolution studies, we found that 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. Different VSDs vary not only in the length of the region where the electric field is focused but also differ in their overall electrostatics, with possible implications in the diverse ion selectivity of their gating pores. Due to state-dependent field reshaping, not only translocated basic but also relatively immobile acidic residues contribute significantly to the gating charge. In the case of NavAb, we found that the transition between structurally resolved activated and resting states results in a gating charge of , which is noticeably lower than experimental estimates. Based on the analysis of VSD electrostatics in the two activation states, we propose that the VSD likely adopts a deeper resting state upon hyperpolarization. In conclusion, our results provide an atomic-level description of the gating charge, demonstrate diversity in VSD electrostatics, and reveal the importance of electric-field reshaping for voltage sensing in Nav channels.
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