Actions of ATX-II and other gating-modifiers on Na+ currents in HEK-293 cells expressing WT and ΔKPQ hNaV 1.5 Na+ channels

Voltage-gated Na+ channels underlie the action potential upstroke in excitable cells, and both natural and synthetic inactivation inhibitors prolong the Na+ current (INa). The effects of Na+ channel mutations on these pharmacological actions are incompletely investigated. Therefore, I compared the effects of inactivation inhibitors on INa in WT or mutant (ΔKPQ) human cardiac Na+ channels expressed in HEK-293 cells, by measuring difference currents sensitive to 50 μM tetrodotoxin. Veratridine and the pyrethroid tefluthrin prolonged INa in WT and ΔKPQ without obvious differential effects, while a sea anemone toxin (ATX-II) and a synthetic inotrope (SDZ 201-106) prolonged WT INa, but apparently blocked INa in the ΔKPQ mutant. This block was due, at least in-part, to enhanced steady-state inactivation, with half-inactivation potentials shifted by up to −17 mV. Inactivation enhancement by ATX-II also persisted when conditioning depolarizations were abbreviated, and was unaffected by the additional presence of SDZ 201-106 consistent with these agents having unique interactions with ΔKPQ Na+ channels. It is concluded that the toxin-binding sites for ATX-II and SDZ 201-106 have allosteric effects converging on a common path affecting steady-state inactivation of ΔKPQ INa. Pharmacological modulation of this path to increase inactivation in mutant Na+ channels could potentially produce therapeutic benefits.