Actions of ATX-II and other gating-modifiers on Na(+) currents in HEK-293 cells expressing WT and DeltaKPQ hNa(V) 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 (I(Na)). The effects of Na(+) channel mutations on these pharmacological actions are incompletely investigated. Therefore, I compared the effects of inactivation inhibitors on I(Na) in WT or mutant (DeltaKPQ) human cardiac Na(+) channels expressed in HEK-293 cells, by measuring difference currents sensitive to 50muM tetrodotoxin. Veratridine and the pyrethroid tefluthrin prolonged I(Na) in WT and DeltaKPQ without obvious differential effects, while a sea anemone toxin (ATX-II) and a synthetic inotrope (SDZ 201-106) prolonged WT I(Na), but apparently blocked I(Na) in the DeltaKPQ mutant. This block was due, at least in-part, to enhanced steady-state inactivation, with half-inactivation potentials shifted by up to -17mV. 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 DeltaKPQ 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 DeltaKPQ I(Na). Pharmacological modulation of this path to increase inactivation in mutant Na(+) channels could potentially produce therapeutic benefits.