sodium channel type IV Inhibitors

Chemical inhibitors of sodium channel type IV include a variety of compounds that bind to different sites on the protein, each leading to inhibition of its function. Tetrodotoxin and saxitoxin are potent inhibitors that physically occlude the pore of the sodium channel. They bind to a site that is accessible from the extracellular side when the channel opens, and their binding prevents sodium ions from passing through the channel, which inhibits the generation and propagation of action potentials. μ-Conotoxin GIIIB operates similarly, by selectively binding to and obstructing the channel to inhibit neuronal signaling. These inhibitors directly block the ion-conducting pore, thereby halting the normal activity of the channel.

Other inhibitors, such as aconitine and batrachotoxin, interact differently with sodium channel type IV. Aconitine binds to the channel and induces a state that eventually leads to channel inactivation, despite initially activating it. Batrachotoxin, on the other hand, forces the channel to remain open, preventing normal closure and inactivation, leading to desensitization and functional inhibition of the channel. Both of these compounds cause an initial increase in sodium conductance, but the end result is the channel becoming non-functional due to the inability to recover from the inactivated or desensitized state. Similarly, veratridine keeps the channel open, but its action disrupts normal inactivation, leading to prolonged depolarization that ultimately inhibits normal channel function. Lidocaine, phenytoin, carbamazepine, and lamotrigine all preferentially stabilize the inactive form of sodium channel type IV, blocking nerve impulse conduction or reducing neuronal firing by keeping the channel in a state that cannot be activated. Lastly, riluzole and ranolazine act indirectly; riluzole enhances the inactivation of sodium channel type IV, reducing excitability and neurotransmitter release, whereas ranolazine selectively inhibits late-phase inward sodium current, which leads to inhibition of sodium channel type IV during pathological conditions without interfering with normal electrical conduction. Each of these inhibitors interacts with the sodium channel type IV in a manner that leads to the reduction of its normal activity.