Sodium channel activators: Model of binding inside the pore and a possible mechanism of action

Abstract

Sodium channel activators, batrachotoxin and veratridine, cause sodium channels to activate easier and stay open longer than normal channels. Traditionally, this was explained by an allosteric mechanism. However, increasing evidence suggests that activators can bind inside the pore. Here, we model the open sodium channel with activators and propose a novel mechanism of their action. The activator-bound channel retains a hydrophilic pathway for ions between the ligand and conserved asparagine in segment S6 of repeat II. One end of the activator approaches the selectivity filter, decreasing the channel conductance and selectivity. The opposite end reaches the gate stabilizing it in the open state.

K+ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases

“…355 On the basis of the ternary-complex idea, a new mechanism of action of these important pharmacological tools was proposed, according to which a Na + channel agonist molecule binds in the central pore but leaves a path for ion permeation between its nucleophilic face and a nucleophilic residue in the inner pore. 353 Subsequent mutational, electrophysiological, and ligand-binding experiments confirmed important predictions of the new model of action of sodium agonists. [356][357][358] Two other classes of oxygen-rich natural products that potently block K V 1.3 channels are psoralens and khelliones bearing lipophilic phenylalkyl or phenoxyalkyl side-chains.…”

“…[347][348][349] A number of ion channel models with pore-bound ligands chelating metal ions further support the possible involvement of metal ions in ligand-receptor complexes. 22,343,[350][351][352][353] For Na + channels, a recent model explained the intriguing observation that two molecules of the nucleophilic local anesthetic benzocaine bind to a site, where a single molecule of a cationic local anesthetic ligand, such as lidocaine binds. 354 According to a classical concept, batrachotoxin, veratridine, and other Na + channel agonists activate Na + channels allosterically.…”

The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides

“…S3). Such a binding mode is proposed for sodium channel agonists like batrachotoxin (26,27), but cationic antagonists such as LAs block the permeation by the electrostatic mechanism (13,14). The fact that cationic LAs and electroneutral DCJW have common pore-facing ligand-sensing residues F 4i15 , V 4i18 , and Y 4i22 and that these ligands apparently target the same region in the inner pore is a paradox.…”

Kinetic Analysis of Membrane Potential Dye Response to NaV1.7 Channel Activation Identifies Antagonists with Pharmacological Selectivity against NaV1.5

“…Recent publications indicate that compound 2 has a distinct binding mode, interacting with the voltage-sensing domain of domain IV, 21 compared with channel pore-binding sites for local anesthetics 24 and veratridine. 25 Whether this unique binding mode for compound 2 explains why a delay in response to veratridine induced depolarization in a cell that is not under voltage-clamp is yet to be determined.…”