Physiology, Sodium Channels

Excerpt

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.

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.

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.