Voltage-gated sodium channels are membrane-embedded proteins complexes that allow rapid flow of sodium ions across an electrochemical gradient into the plasma membrane through a pore. This way, they help in generating action potential.
How do these membrane proteins look like? The significant alpha subunits of voltage-gated sodium channels consist of four connected domains – DI to DIV – each of which consists of six transmembrane segments – S1- S6. Sodium ions flow into the cell through the pore domain or the gate, constituting segments S5 and S6 (PM). Segments S1-S4 make the voltage-sensing domain (VSD), and S4 is the voltage sensor comprising of basic amino acids such as Lys and Arg, besides other residues; upon depolarization the voltage-sensing domain undergoes conformational changes as the positive charges move up. The structural rearrangement passes through the S4-S5 linker to the pore domain, thus opening the channel gate.
The sodium channels exist in three different states: open or activated; inactivated; closed or resting. When membrane depolarization occurs, the channels open and sodium ions rush into the cell. Immediately afterwards, the inactivation gate – the ball and chain - blocks the flow of ions. As the cell membrane returns to its resting potential, the sodium channel goes back to its closed or resting state.
In humans, these channels are present in the central nervous system, the peripheral nervous system, the muscles, and the heart: Nav1.1, Nav1.2, Nav1.3, Nav1.6 – central nervous system; Nav1.7, Nav1.8, Nav1.9 – peripheral nervous system; Nav1.4 – skeletal muscles; Nav1.5 – heart muscles. Defects in sodium channels can lead to heart diseases, pain dysregulation, skeletal muscle defects, cancer, and various neurological disorders such as epilepsy; hence they are important drug targets.
Sodium channels are targeted by many small and large molecules - the family of peptide toxins from animals such snakes, spiders, snails, scorpions, and sea-anemones being few of them. Some of these toxins block the pore and stop the flow of ions; the other group of toxins modulate the gating properties of the channel by interacting with the voltage-sensing domain and changing the channel conformation.
References
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