RT Journal Article
SR Electronic
T1 Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na+ Channels
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.099580
DO 10.1124/mol.115.099580
A1 Vaibhavkumar S. Gawali
A1 Peter Lukacs
A1 Rene Cervenka
A1 Xaver Koenig
A1 Lena Rubi
A1 Karlheinz Hilber
A1 Walter Sandtner
A1 Hannes Todt
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/09/10/mol.115.099580.1.abstract
AB The clinically important suppression of high-frequency discharges of excitable cells by local anesthetics (LA) is largely determined by drug-induced prolongation of the time course of repriming (recovery from inactivation) of voltage-gated Na+ channels. This prolongation may result from periodic drug-binding to a high-affinity binding site during the action potentials and subsequent slow dissociation from the site between action potentials ("dissociation hypothesis"). For many drugs the fast inactivated state has been suggested to represent the high-affinity binding state. Alternatively, LAs may bind with high affinity to a native slow inactivated state, thereby accelerating the development of this state during action potentials ("stabilization hypothesis"). In this case, slow recovery between APs occurs from enhanced native slow inactivation. In order to test these two hypotheses we produced serial cysteine mutations of the domain IV S6 segment in rNav1.4 which resulted in constructs that had varying propensities to enter fast and slow inactivated states. We tested the effect of the LA lidocaine on the time course of recovery from short and long depolarizing prepulses which, under drug-free conditions, recruited mainly fast and slow inactivated states, respectively. Among the tested constructs the mutation-induced changes in native slow recovery induced by long depolarizations were not correlated with the respective lidocaine-induced slow recovery after short depolarizations. On the other hand, for long depolarizations the mutation-induced alterations in native slow recovery were significantly correlated with the kinetics of lidocaine-induced slow recovery. These results favor the "dissociation hypothesis" for short depolarizations but the "stabilization hypothesis" for long depolarizations.