Lidocaine Block of LQT-3 Mutant Human Na ⁺ Channels

Abstract

In transiently transfected mammalian cells we have identified pharmacological consequences of a naturally occurring deletion mutation, delta KPQ, of the human heart Na+ channel alpha subunit that previously has been linked to one form of the long QT syndrome, an inherited heart disease. Our results show that the Class IB antiarrhythmic agent lidocaine blocks maintained inward current through and slows recovery from inactivation of delta KPQ-encoded Na+ channels. Block is greater for maintained than for peak current. Because incomplete inactivation of mutant Na+ channels is now thought to underlie the prolonged ventricular action potential, which is the phenotype of this disease, and we find that the delta KPQ mutation speeds the recovery from inactivation of drug-free mutant channels, our results provide evidence, for the first time, that clinically relevant dysfunctional properties of an ion channel can be selectively targeted on the basis of the molecular properties conferred on the channel by an inherited genetic disorder.

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

“…This behavior of lidocaine is also consistent with the experiments done earlier as was previously reported that lidocaine was more effective in late component of Na C current than peak current in DKPQ channels expressed in mamalian cells. 45,46,47,48,49 Lidocaine preferentially blocked late over peak current and the blockade was equally effective in all 3 channels having mutations N1325S, R1644H and DKPQ expressed in Xenopus oocytes. 50 Lidocaine inhibits dispersed reopening in single channels without affecting mean open times.…”

“…Clinical studies showed that the late current is more sensitive than peak current to block by class Ib 51 antiarrhythmic drugs like lidocaine. 45,47,52 Next we have studied the nonequilibrium thermodynamics of the system in presence of drug. Here we assume that the system is in contact with an isothermal bath at temperature T. The total internal energy U(t), the free energy, F(t) and the system entropy, S(t) is given as follows: 53…”

Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes

“…Pclamp8 (Axon Instruments, Foster City, CA), Excel (Microsoft, Seattle, WA), and Origin6 (Microcal Software, Northampton, MA) were used for data acquisition and analysis. Data for the voltage dependence of activation were fitted with Boltzmann relationships, and data for the time course of recovery from inactivation were fitted with functions of two exponentials using Origin as described previously by us (23). Data are presented as mean values Ϯ S.E.…”

“…Data are presented as mean values Ϯ S.E. Two-tailed Student's t test was used to compare means; p Ͻ 0.05 was considered statistically significant (23).…”

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

“…promise of personalized disease management (Schwartz et al, 1995;An et al, 1996;Moss and Kass, 2005). However, particularly in the case of LQTS, patients with multiple mutations have more severe clinical phenotypes and may respond uniquely to pharmacologic therapies (Westenskow et al, 2004;Itoh et al, 2010;Zhang et al, 2012).…”