A revised view of cardiac sodium channel “blockade” in the long-QT syndrome
Nicholas G. Kambouris, … , Gordon F. Tomaselli, Jeffrey R. Balser
Nicholas G. Kambouris, … , Gordon F. Tomaselli, Jeffrey R. Balser
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):1133-1140. https://doi.org/10.1172/JCI9212.
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Article

A revised view of cardiac sodium channel “blockade” in the long-QT syndrome

Abstract

Mutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a form of the congenital long-QT syndrome (LQT3) that provokes lethal ventricular arrhythmias. These autosomal dominant mutations disrupt Na channel function, inhibiting channel inactivation, thereby causing a sustained ionic current that delays cardiac repolarization. Sodium channel–blocking antiarrhythmics, such as lidocaine, potently inhibit this pathologic Na current (INa) and are being evaluated in patients with LQT3. The mechanism underlying this effect is unknown, although high-affinity “block” of the open Na channel pore has been proposed. Here we report that a recently identified LQT3 mutation (R1623Q) imparts unusual lidocaine sensitivity to the Na channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicate that the open-time distribution is not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening (“closed-state inactivation”), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulates the effects of lidocaine on pathologic INa. These findings explain the unusual drug sensitivity of R1623Q and provide a general and unanticipated mechanism for understanding how Na channel–blocking agents may suppress the pathologic, sustained Na current induced by LQT3 mutations.

Authors

Nicholas G. Kambouris, H. Bradley Nuss, David C. Johns, Eduardo Marbán, Gordon F. Tomaselli, Jeffrey R. Balser

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Figure 7

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Three-state Markov gating models with state-dependent lidocaine binding....
Three-state Markov gating models with state-dependent lidocaine binding. The symbols C, O, and I represent the aggregate closed, open, and inactivated states of the channel, respectively. (a) One-affinity (model I) and 2-affinity (model II) schemes of lidocaine binding were assessed. For the wild-type channel, the rate constants used for the gating transitions upon depolarization were as follows (s–1): kCO (that is, closed → open) = 665, kOC = 492, kOI = 1998, kIO = 2.9, kCI = 66. The magnitude of kIC was determined by microscopic reversibility constraints: kIC = kOCkCIkIO/(kOCkOI). For R1623Q, differences from wild-type were kOI = 658 and kCI = 492. For LQT3, the only difference from wild-type was kIO = 55. For models I and II, the on-rate constants for drug binding were always 1 × 108 s–1M–1. In model II, the off-rate constant for lidocaine binding to the C state (kCoff) was 128,027 s–1 (Kd 1.3 mM). In models I and II, the off-rate constant for lidocaine binding to the I state (kIoff) was 383 s–1 (Kd 4 μM). In both models, we assumed that lidocaine binding did not slow the rate constant for recovery from inactivation as recently shown (38). Hence, kIL→CL was equal to kIC. The forward rate constant for closed-state inactivation when lidocaine is bound (kCL→IL) was entirely determined (through microscopic reversibility) by the off rates for drug binding to the closed and inactivated states and the drug-free rate of closed-state inactivation as follows: kCL→IL = kCIkCoff/kIoff. Because kIoff < kCoff, the rate of closed-state inactivation is increased when drug is bound (i.e., kCL→IL > kCI). (b) Simulated sodium currents from models I and II (see text).