Introduction

There are two major classes of sodium channels in mammals: The voltage-gated sodium channel (VGSC) family and the epithelial sodium channel (ESC). Voltage-gated sodium channels exist throughout the body in various cell types, while epithelial sodium channels are located primarily in the skin and kidney. The generic term "sodium channel" most often refers to voltage-gated sodium channels and their role in propagating action potentials and will be the topic of discussion for this article. However, it is important to note that there are many variations of the sodium channel with various functions not discussed here. Examples of such variations are alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and nicotinic sodium receptors that are both ligand-gated.

Voltage-gated sodium channels are transmembrane proteins that open when the membrane potential in their vicinity become depolarized, allowing the flow of sodium from the region of higher concentration (usually the exterior of the cell at the resting potential) to the area of lower concentration (usually the interior of the cell.) They are the first channels to open in response to changes in voltage, allowing positively charged sodium ions to accumulate in the interior of the cell. The ability of a cell to depolarize is critical in excitable cells, such as neurons and muscle cells, where this electrical signal can be used to give rise to an action potential that then transforms into a response like the release of neurotransmitters or contraction, respectively.[1]

Voltage-gated sodium channels have two gates: an activating gate that is voltage-dependent and an inactivating gate that is time-dependent. The opening of the activating gate allows the influx of sodium and cell depolarization. The closing of the inactivation gate will stop the flow of sodium regardless of the status of the activation gate. These two gates work in tandem to ensure that depolarization occurs in a controlled manner: after being open for a few milliseconds, the voltage-gated sodium channels will inactivate, stopping the flow of sodium, even in the presence of persistent stimulation. The channel will remain unable to open again until the cell repolarizes to a threshold voltage that varies depending on the cell type. The clinical implication is that in situations of sustained depolarization, the voltage-gated sodium channel will stop working, preventing the cells from becoming more and more positive. This mechanism is an important safeguard to ensure that unimpeded depolarization cannot occur.[2]

To perform their functions, voltage-gated sodium channels must be targeted to specific cellular domains and interact with multiple membrane, extracellular matrix, and cytoskeletal proteins, forming multiprotein complexes. Mutations in different proteins of the complex can result in similar clinical phenotypes because the integrity of the whole complex is fundamental for the function of the voltage-gated sodium channels. 

Mechanism

The structure of voltage-gated sodium channels consists of one pore-forming alpha subunit through which the sodium will pass and one to two beta subunits.

Alpha subunits: The alpha subunits are made up of four transmembrane domains, with each domain consisting of six segments. The voltage sensory component is on the fourth segment of each alpha domain.[3]

Beta subunits: The genes SCN1B–SCN4B encode five identified beta subunits. Interestingly, the beta subunits are actually a part of the Ig superfamily of cell adhesion molecules due to their large, extracellular V-set immunoglobulin (Ig) domain.[4][5] While the beta subunit does not have a sodium channel pore, it is important in regulating excitability by modulating the localization, gating, and kinetics of the pore on the alpha subunit adjacent to it.

Pathophysiology

Research has identified over 200 missense mutations that affect seven different voltage-gated sodium channels that cause excitability disorders or channelopathies. While these disorders are rare, they are an example of how proteins altered by genetic variability and mutations can profoundly affect the functioning of voltage-gated sodium channels. One example of such a mutation is the SCN1A gene, which encodes the NAV 1.1 voltage-gated sodium channel alpha subunit.[2][6] This mutation has been well-studied and has shown to be the etiology for many primary epilepsies, including febrile seizures.[7] Primary epilepsies are epilepsy for which there is no apparent cause, such as cerebral vascular accident, cerebral palsy, or other contributing factors. Since mutated voltage-gated sodium channels are one of the primary causes for epilepsy, it makes sense that many first-line drugs for epilepsy are from the sodium channel blocker class.[8]

Clinical Significance

Dysfunction in voltage-gated sodium channels correlates with neurological and cardiac diseases, including epilepsy, myopathies, and cardiac arrhythmias (long QT, Brugada, sick sinus, and short QT syndromes, among others). The dysfunction can be genetic or acquired, including secondary to toxins. In particular, toxins from marine animals have a preference for blocking voltage-gated sodium channels, resulting in sensory abnormalities (because of dysfunction of sensory neurons) and muscle weakness (from the pathology of the motor neurons and muscle cells). One such toxin is the tetrodotoxin from the Tetraodontidae family, more commonly referred to as pufferfish that store the toxin in high concentrations in its liver.[9] Due to the heat-stable nature of the toxin, it remains active even after cooking and results in the poisoning of those who eat improperly prepared fish. The toxin gets absorbed and travels systemically, where it can bind to sodium channels in a variety of tissues. The prevention of contractility of both cardiac and respiratory myocytes can lead to respiratory arrest and cardiac arrest, leading to possible death. 

Voltage-gated sodium channels are the target of multiple pharmacological compounds, including anesthetics like lidocaine, antiepileptics like phenytoin and lamotrigine, and antiarrhythmics like flecainide and mexiletine. The prevention of nerve conduction is the mechanism of drugs like lidocaine blocks the potentiation of pain signals, while antiepileptics such as phenytoin and lamotrigine lower the seizure threshold by similarly reducing neuron excitability.[10] In all instances, the object is to reduce the influx of sodium to prevent the generation of repeated action potentials by stabilizing the membrane potential. The prevention of action potentials, particularly on the presynaptic neuron, prevents downstream signal transmission by inhibiting the release of neurotransmitters at the synaptic cleft. 

Due to the extensive distribution of sodium channels in a wide array of organ systems, care is necessary when prescribing or administering sodium channel blockers. Lidocaine, for instance, is a potent local anesthetic used routinely for procedures and laceration repairs but does carry the risk for systemic release. High doses of lidocaine released into systemic circulation can be toxic to both the CNS and cardiovascular system causing seizures, AV heart block, arrhythmias, and more.[11]