- 作者: Kun-Chi Chiang; Ling-Ping Lai; Ru-Chi Shieh
- 作者服務機構: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC
- 中文摘要: --
- 英文摘要:
Brugada syndrome is a life-threatening, inherited arrhythmia disorder associated with
autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na+
channel α subunit (Nav1.5). Here, we characterized the biophysical properties of a
novel Brugada syndrome-associated Nav1.5 mutation, A551T, identified in a proband
who was successfully resuscitated from an episode of ventricular fibrillation with
sudden collapse. Whole-cell currents through wild-type (WT) Nav1.5 and mutant
(A551T) channels were recorded and compared in the human embryonic kidney cell
line HEK293T transfected with SCN5A cDNA and SCN1B cDNA, using the
patch-clamp technique. Current density was decreased in the A551T mutant
compared to the WT. In addition, the A551T mutation reduced Nav1.5 activity by
promoting entry of the channel into fast inactivation from the closed state, thereby
shifting the steady-state inactivation curve by -5 mV. Furthermore, when evaluated
at -90 mV, the resting membrane potential, but not at the conventionally used -120 mV,
both the percentage, and rate, of channel recovery from inactivation were reduced in
the mutant. These results suggest that the DI-DII linker may be involved in the
stability of inactivation gating process. This study supports the notion that a
reduction in Nav1.5 channel function is involved in the pathogenesis of Brugada
syndrome. The structural-functional study of the Nav1.5 channel advances our
understanding of its pathophysiolgocial function. - 中文關鍵字: --
- 英文關鍵字: --