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Review
. 2015;9(6):360-6.
doi: 10.1080/19336950.2015.1079674.

Voltage gated sodium channels as drug discovery targets

Sharan K Bagal  1 , Brian E Marron  2 , Robert M Owen  1 , R Ian Storer  1 , Nigel A Swain  1
Affiliations
Review

Voltage gated sodium channels as drug discovery targets

Sharan K Bagal et al. Channels (Austin). 2015.

Abstract

Voltage-gated sodium (NaV) channels are a family of transmembrane ion channel proteins. They function by forming a gated, water-filled pore to help establish and control cell membrane potential via control of the flow of ions between the intracellular and the extracellular environments. Blockade of NaVs has been successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias. First generation sodium channel modulator drugs, despite low inherent subtype selectivity, preferentially act on over-excited cells which reduces undesirable side effects in the clinic. However, the limited therapeutic indices observed with the first generation demanded a new generation of sodium channel inhibitors. The structure, function and the state of the art in sodium channel modulator drug discovery are discussed in this chapter.

Keywords: sodium channel drugs; sodium channel structure; sodium channel toxins; voltage-gated sodium channels Electrophysiology screening.

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Figures

Figure 1.
Figure 1.
NaV channel structural topology, highlighting common ligand binding sites and significant structural features. Domains D1-D4 are represented in different colors while β subunits are shown in gray.
Figure 2.
Figure 2.
Sodium channel states: NaV channels cycle between 3 states: open, closed (resting) and inactivated. They cycle from the closed (resting) state to the open state upon membrane depolarisation. The channel is open for less than a millisecond prior to inactivation. The inactivated state reprimes to the resting state when the cell membrane potential has returned to a hyperpolarised resting potential. Sodium channel current: The current associated with the cycling of sodium channels through the resting, open and inactivated state.
Figure 3.
Figure 3.
Selected toxin modulators.
Figure 4.
Figure 4.
Selected first generation sodium channel modulator drugs.
Figure 5.
Figure 5.
Early examples of second generation sodium channel modulators.
Figure 6.
Figure 6.
Examples of NaV subtype selective targeting modulators.
See this image and copyright information in PMC

References

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