Abstract
Na+ channel α-subunit, Nav1.5, is the main Na+ channel subunit in the mammalian heart. In the current study, Zhu et al (JCI Insight 2021;6:143092, PMID 34156986) examine the impact of accessory Navβ1 and Navβ3 subunits on Nav1.5 responses to 2 class Ib antiarrhythmics, lidocaine and ranolazine. Both drugs stabilize the activated conformation of the voltage sensor of domain-III (DIII-VSD) in Nav1.5. However, Navβ1 differentially modulates the effects of lidocaine and ranolazine on the Nav1.5 voltage sensing domain. The authors also took advantage of the Scn1b-null mouse model to show that loss of Scn1b (Navβ1) differentially affects the potencies of lidocaine and ranolazine, as well as modulation by Navβ1 on drug responses at the whole-heart level. SCN1B transcript expression was 3 times higher in human atria compared to the ventricles. The authors conclude that β subunits of cardiac Na+ channels play critical roles in differentially modulating the efficacy of antiarrhythmic drugs; therefore, patient-to-patient differences in β-subunit expression are likely to have a significant impact on therapeutic outcomes.
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