Small molecule modulation of voltage gated sodium channels

Abstract

Voltage gated sodium channels are fundamental players in animals physiology. By triggering the depolarization of the lipid membrane they enable generation and propagation of the action potential. The involvement of these channels in numerous pathological conditions makes them relevant target for pharmaceutical intervention. Therefore, modulation of sodium conductance via small molecule binding constitutes a promising strategy to treat a large variety of diseases. However, this approach entails significant challenges: voltage gated sodium channels are complex nanomachines and the details of their workings have only recently started to become clear. Here we review - with emphasis on the computational studies - some of the major milestones in the long-standing search of a quantitative microscopic description of the molecular mechanism and modulation of voltage-gated sodium channels.

Figure 1

Cartoon representation of the structure and mechanism of voltage gated sodium channels. The first four transmembrane (TM) helices (S1 through S4 from each subunit) constitute the voltage sensor domain (purple). The pore domain, instead, comprises two TM helices, S5 and S6 (blue and yellow, respectively. The pore and voltage sensor domains are connected by the linker domain (red). (B) The gating mechanism of VGSCs requires a coordinated motion of the voltage sensor and pore domains. Under depolarizing conditions, the positively charged S4 helix translates along the bilayer normal causing the splaying of the S6 helix bundle. The channel thus transitions from the closed (C) to the open state (O). The latter is unstable and decays to the inactivated state (I), a nonconductive state characterized by an activated voltage sensor domain and a closed pore domain.

Figure 2

Binding of the inhalational general anesthetic isoflurane to the voltage gated sodium selective bacterial channel NaChBac. A) An isoflurane molecule diffusing in and out of the pore of NaChBac through adjacent fenestrations. The channel cavity is rendered as a solid grey surface. B) The three binding sites identified by clustering analysis: extracellular site (red), linker site (yellow) and cavity site (purple/green).