Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of two well-known Class-Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, Nav1.5, expressed in mammalian heart. We show that both drugs stabilize the activated conformation of the voltage-sensor of in Domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main Class-Ib drug binding site, F1760, affected but did not abolish, the modulation of drug block by Navβ1/β3. Recordings from adult mouse ventricular myocytes demonstrated that Scn1b (Navβ1) loss of differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to intraperitoneal injection of ranolazine or lidocaine in WT and Scn1b null animals, suggesting that NaVβ1 modulates drug responses at the whole heart level. In human heart, we found that SCN1B transcript expression is three times higher in atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically impact patient response to Class-Ib antiarrhythmic therapies.
Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva