A revised view of cardiac sodium channel "blockade" in the long-QT syndrome.
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.
Kambouris
N G
NG
Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nuss
H B
HB
Johns
D C
DC
Marbán
E
E
Tomaselli
G F
GF
Balser
J R
JR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008012:Lidocaine