Research & Drug Development

Voltage-gated sodium channels (VGSC) are critical elements of action potential initiation and propagation in excitable cells because they are responsible for the initial depolarization of the membrane. Sodium channels consist of a highly processed large a subunit, (approximately 260 kDa), associated with auxiliary b subunits. The a subunit is formed by 4 polypeptide domains similar to each other (I-IV), each containing 6 (S1-S6) regions. An hydrophobic loop between segments 5 and 6 is thought to dip into the membrane to line the pore itself. In addition to forming the pore, the loop acts as ion selectivity filter. The S4 segment of each domain function as voltage sensor, containing positive charged residues that are proposed to move upon depolarization, causing a conformational change that open the channel. The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate, folding into the channel structure and blocking the pore from the inside during sustained depolarization of the membrane.

Nine genes (SCN1A, SCN2A, etc.) encoding distinct a subunits (Nav1.1-Nav1.9) have been identified and  functionally characterized. Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7 are highly tetrodotoxin-sensitive and broadly expressed in neurons. Nav1.5, NaV1.8, Nav1.9 are tetrodotoxin-resistant to varying degrees, due to changes in amino acid sequence at a single position in domain I, and they are highly expressed in heart and dorsal root ganglion (DRG) neurons. The isoform Nav1.4, is expressed primarily in skeletal muscle.

The pore-forming a subunit is sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the b subunits.

All of the pharmacological agents that act on sodium channels have receptor sites on the a subunits. At least six distinct receptor sites for neurotoxins and one receptor site for local anesthetics and related drugs have been identified.

The kinetic characteristics of the VGSCs include a rapid opening upon depolarization of the cell membrane (activation), and an equally rapid inactivation of the channels. A refractory period follows, in which  VGSCs cannot re-open until the membrane is repolarized and they recovery from inactivation.

Blockade by different drugs targeting VGSCs varies with structure and physical properties of the drug and the type of channel, and depends on the membrane state. If the block is relatively weak at resting, but strong during depolarization, this suggest strong activity of the drug  in pathological conditions, leaving normal function unaffected.