Human Voltage-Gated Sodium Channel (Nav1.7)

Maeve Griffin '23 & Hannah Schmidt '22

Contents:

I. Introduction

Voltage-gated sodium channels are transmembrane ion channels that play a central role in neuronal firing of the action potential. Action potentials underlie all neuronal communication within the brain and consist of a wave of electrical energy that sweeps down a single neuron and causes neurotransmitter release at the presynaptic terminal. Firing of an action potential begins when voltage-gated sodium channels detect a depolarization of the neuron's membrane potential. This change in voltage opens these channels, allowing Na+ ions to rush into the neuron and depolarize it further. Once the neuron has reached a peak threshold voltage, these channels close and inactivate temporarily to prevent another action potential from refiring right away.  

Members of the voltage-gated sodium channel family exhibit varied functions. This molecule, NaV1.7, is involved in the pain sensation - NaV1.7 mutations have been connected to both increased and decreased pain sensitivity. NaV channels also have significant potential to be acted on by drugs and toxins - this molecule is shown in contact with toxins that alter pain perception.

II. General Structure

This voltage-gated sodium channel is a hetero 3-mer, with a total weight of 283 kDa. This channel consists of a 260 kDa core alpha subunit to which two auxiliary beta subunits, beta-1 and beta-2, are attached. The alpha subunit of all voltage-gated sodium channels forms the channel's pore, and one or more beta subunits may help position the protein in the membrane or otherwise alter function.

The alpha subunit folds into four repeated domains (I, II, III, and IV), each containing six transmembrane helices (S1-6) that span the lipid bilayer of the neuron.

The S1-4 region acts as the voltage-sensing domain (VSD), with the positively-charged, fourth transmembrane helix (S4) specifically serving as a voltage-sensor that detects external changes in membrane potential and allows for the voltage-gating function of this channel. The VSD may occupy either an activated or inactivated state; this determines whether the channel opens or closes.

S5-6 helices comprise the pore domain, and between them resides a hydrophobic stretch of amino acids that form the channel's pore loop (through which Na+ ions can enter). The size and charge of this loop allows for the ion specificity of the channel, specifically in the function of the selectivity filter region.

Movement of the channel between open and closed conformations occurs due to the coupling of the the voltage-sensing domain and pore domains of each of the four subunits. Change from a closed to an open conformation results in the influx of Na+ ions we see during action potential. The structure shown here is in its closed conformation.

III. Voltage Sensing

The S4 segment of the voltage-sensing domain serves as the channel's voltage-sensor. All four of these segments contain repeated motifs including one positively charged amino acid, followed by two hydrophobic amino acids. This motif manifests as a helical arrangement of positive residues across the neuronal membrane. Depolarization induces a conformational change in which this helix rotates and moves outward, subsequently opening the channel pore for Na+ ions to enter.

IV. Na+ Selectivity

The helices of S5-6 form a loop within the channel's transmembrane region, which serves a selective pore for Na+ ions. Each of the four regions that make up the selectivity filter contains one of a conserved series of amino acids, Asp-Glu-Lys-Ala (DEKA), that are responsible for Na+ ion selectivity. The location of the DEKA residue in each repeat is termed the SF locus. The DEKA motif is common among proteins with Na+ selectivity.

IV. Interactions with Toxins

The NaV1.7 ion channel includes several small openings that can be penetrated by fatty acid chains.

This molecule is in complex with a small molecule called saxitoxin. Saxitoxin (C10H17N7O4) is a pore blocker, one of the two main classes of drugs and toxins that target voltage-gated sodium channels. Saxitoxin binds in the pore at a conserved location in VSDIII. Specifically, Thr1409 and Ile1410 interact with the toxin in the pore.

VI. References

Luo, L. (2016). Chapter 2 - Signaling Within Neurons. Principles of Neurobiology. Garland Science.

Tsai, C-J., Tani, K., Irie, K., Hiroaki, Y., Shimomura, T., McMillan, DG., et al. (2013). Two Alternative Conformations of a Voltage-Gated Sodium Channel. Journal of Molecular Biology, 425(22), 4074-88.

Shen, H., Liu, D., Wu, K., Lei, J., and Yan, N. (2019). Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, 363(6433), 1303–1308.

Shen, H., Zhou, Q., Pan, X., Li, Z., Wu, J., and Yan, N. (2017). Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science, 355(6328).

Yu, F.H., Catterall, W.A. (2003). Overview of the voltage-gated sodium channel family. Genome Biol 4(207).

Back to Top