Cardiac Na ⁺ Channel Dysfunction in Brugada Syndrome Is Aggravated by β ₁ -Subunit

Abstract

Background-Mutations in the gene encoding the human cardiac Na ϩ channel ␣-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary ␤ 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 ϩ 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 ␤ 1 -subunit (h␤ 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␤ 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␤ 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 ␣-/␤ 1 -subunit association in the mutant. (Circulation. 2000;101:54-60.)

Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation

“…Site-directed mutagenesis of hH1 was performed by an overlapextension PCR strategy, as described. 15 A 183-bp HincII/SacII fragment (No. 5290-5473 of hH1) of the mutant PCR fragment was subcloned back into the pRcCMV-WT plasmid to generate a mutant plasmid pRcCMV-L1825P.…”

Post-transcriptional alterations in the expression of cardiac Na+ channel subunits in chronic heart failure

“…The auxiliary β1-subunit has been implicated in regulation of Na v 1.5 kinetics associated with the LQT3 mutation 15 , aggravation of NaCh dysfunction in Brugada syndrome 16 , modification of block of NaCh by fatty acids 17 and lidocaine 18 , and modulation of trafficking of Na v 1.5 19 . The physiological role of the β 2 subunit in heart is still under investigation, but it is known that to play a role in cell adhesion.…”

Expression and Intracellular Localization of an SCN5A Double Mutant R1232W/T1620M Implicated in Brugada Syndrome

“…7,12,13 Several recent studies have characterized a threonine-tomethionine mutation at position 1620 (T1620M) in SCN5A, found in Brugada syndrome patients. 5,10,[13][14][15][16] This mutation is located in the S3-S4 extracellular loop in domain IV of the hNa v 1.5. However, this mutation is also found in the presence of second mutation (R1232W) on the same allele of all affected individuals and located on S1-S2 extracellular loop in domain III.…”