Enhanced Na(+) channel intermediate inactivation in Brugada syndrome.
Brugada syndrome is an inherited cardiac disease that causes sudden death related to idiopathic ventricular fibrillation in a structurally normal heart. The disease is characterized by ST-segment elevation in the right precordial ECG leads and is frequently accompanied by an apparent right bundle-branch block. The biophysical properties of the SCN5A mutation T1620M associated with Brugada syndrome were examined for defects in intermediate inactivation (I:(M)), a gating process in Na(+) channels with kinetic features intermediate between fast and slow inactivation. Cultured mammalian cells expressing T1620M Na(+) channels in the presence of the human beta(1) subunit exhibit enhanced intermediate inactivation at both 22 degrees C and 32 degrees C compared with wild-type recombinant human heart Na(+) channels (WT-hH1). Our findings support the hypothesis that Brugada syndrome is caused, in part, by functionally reduced Na(+) current in the myocardium due to an increased proportion of Na(+) channels that enter the I:(M) state. This phenomenon may contribute significantly to arrhythmogenesis in patients with Brugada syndrome. The full text of this article is available at http://www.circresaha.org.
Wang
D W
DW
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Makita
N
N
Kitabatake
A
A
Balser
J R
JR
George
A L
AL
D019943:Amino Acid Substitution; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D002037:Bundle-Branch Block / Q000209:etiology; D002460:Cell Line; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005799:Genes, Dominant; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011930:Reaction Time / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013577:Syndrome; D013696:Temperature; D014162:Transfection; D014693:Ventricular Fibrillation / Q000150:complications / Q000235:genetics / Q000378:metabolism*
D062554:NAV1.5 Voltage-Gated Sodium Channel; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium