Sodium channel activators: model of binding inside the pore and a possible mechanism of action.
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.
Tikhonov
Denis B
DB
Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
Zhorov
Boris S
BS
D001496:Batrachotoxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport; D002414:Cations, Monovalent / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D012964:Sodium / Q000378:metabolism; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000737:chemistry*; D014701:Veratridine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D001496:Batrachotoxins; D002414:Cations, Monovalent; D008024:Ligands; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014701:Veratridine; D012964:Sodium