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

Background-Mutations in the gene encoding the human cardiac Na+ channel alp ha-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliar y beta(1)-subunit, widely expressed in excitable tissues, shifts the voltag e dependence of steady-state inactivation toward more negative potentials a nd restores normal gating kinetics of brain and skeletal muscle Na+ channel s expressed in Xenopus oocytes but has little if any functional effect on t he cardiac isoform. Here, we characterize the altered effects of a human be ta(1)-subunit (h beta(1)) on the heterologously expressed hH1 mutation (T16 20M) previously associated with IVF. Methods and Results-When expressed alone in Xenopus oocytes, T1620M exhibit ed no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V-1/2) was significantly shifted to ward more positive potentials than for wild-type hH1. Coexpression of h bet a 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 th e 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 s evere functional defect that results in a greater overlap in the relationsh ip 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.