Physiology, 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]