Physiology, Sodium Channels

Excerpt

There are 2 major classes of sodium channels in mammals: The voltage-gated sodium channel (VGSC) family and the epithelial sodium channel. 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, which is the focus of this discussion. 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 include alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and nicotinic sodium receptors, both of which are ligand-gated.

Voltage-gated sodium channels are transmembrane proteins that open when the membrane potential in their vicinity becomes 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 give rise to an action potential that then triggers responses such as neurotransmitter release or contraction.

Voltage-gated sodium channels have 2 gates: an activating gate that is voltage-dependent and an inactivating gate that is time-dependent. The opening of the activating gate allows sodium influx and cell depolarization. Closing the inactivation gate stops the flow of sodium regardless of the activation gate's status. These 2 gates work in tandem to ensure that depolarization occurs in a controlled manner: after opening for a few milliseconds, the voltage-gated sodium channels inactivate, halting sodium influx, even in the presence of persistent stimulation. The channel remains closed until the cell repolarizes to a threshold voltage that varies with cell type. The clinical implication is that during sustained depolarization, the voltage-gated sodium channel stops functioning, preventing the cells from becoming increasingly depolarized. This mechanism is an important safeguard against unimpeded depolarization.

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 within the complex can result in similar clinical phenotypes because the integrity of the entire complex is fundamental to the function of the voltage-gated sodium channels.