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

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

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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 (I(Na)) 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 I(Na). 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.

Original languageEnglish (US)
Pages (from-to)1133-1140
Number of pages8
JournalJournal of Clinical Investigation
Volume105
Issue number8
DOIs
StatePublished - Apr 2000

ASJC Scopus subject areas

  • Medicine(all)

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    Kambouris, N. G., Nuss, H. B., Johns, D. C., Marbán, E., Tomaselli, G. F., & Balser, J. R. (2000). A revised view of cardiac sodium channel 'blockade' in the long-QT syndrome. Journal of Clinical Investigation, 105(8), 1133-1140. https://doi.org/10.1172/JCI9212