Cardiac Na+ channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit

Article

关键词: LONG QT SYNDROME;    ST SEGMENT ELEVATION;    ALPHA-SCORPION TOXIN;    SODIUM-CHANNEL;    MOLECULAR DETERMINANTS;    SKELETAL-MUSCLE;    VENTRICULAR-FIBRILLATION;    FUNCTIONAL EXPRESSION;    BETA-1 SUBUNITS;    INACTIVATION;   

DOI  :  10.1161/01.CIR.101.1.54

来源: SCIE

【 摘 要 】

Background-Mutations in the gene encoding the human cardiac Na+ channel alpha-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary beta(1)-subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na+ channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human beta(1)-subunit (h beta(1)) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF. Methods and Results-When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V-1/2) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of h beta 1 did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V-1/2 and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal. Conclusions-It is suggested that coexpression of h beta(1) exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered alpha-/beta(1)-subunit association in the mutant.

【 授权许可】

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