Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits
Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva
Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva
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Research Article Cardiology Therapeutics

Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits

Abstract

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 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of 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 loss of Scn1b (NaVβ1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that NaVβ1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.

Authors

Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva

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Figure 5

Scn1b-null LV myocytes show reduced lidocaine but enhanced ranolazine responses.

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Scn1b-null LV myocytes show reduced lidocaine but enhanced ranolazine r...
(A) TB of INa by 100 μM lidocaine was slightly reduced in Scn1b-null compared with WT mouse LV myocytes. (B) Percentage of late INa block by 100 μM lidocaine was markedly lower in Scn1b-null compared with WT mouse LV myocytes. Late INa was measured 30 ms after the onset of the depolarizing voltage step. (C) TB of INa by 100 μM ranolazine was greater in Scn1b-null compared with WT mouse LV myocytes. (D) Percentage of late INa block by 100 μM ranolazine was greater in Scn1b-null compared with WT mouse LV myocytes. (E) Dose-response curve (top) and example traces (bottom) for UDB of INa by lidocaine. UDB was examined by measuring INa evoked in response to 8 repetitive (400 ms duration) depolarizations presented at 2 Hz, which determines the initial rate of UDB. The EC50 for UDB of INa by lidocaine was lower in WT compared with Scn1b-null suggesting that NaVβ1 enhances the sensitivity to lidocaine. (F) Dose-response curve (top) and example traces (bottom) for UDB of INa by ranolazine. In contrast to lidocaine, the EC50 for UDB by ranolazine was higher in WT compared with Scn1b-null, suggesting NaVβ1 reduces the effects of ranolazine. (G) Frequency-dependent UDB block of INa by 10 μM lidocaine in WT and Scn1b-null LV myocytes. UDB was assessed by measuring INa evoked by repetitive depolarizing pulses at 5 Hz (25 ms, 40 pulses), 10 Hz (25 ms, 40 pulses), and 2 Hz (400 ms, 8 pulses). Normalized currents indicate INa(last-pulse)/INa(first-pulse). (H) Frequency-dependent UDB block of INa by 10 μM ranolazine in WT and Scn1b-null LV myocytes. Each data set represents mean ± SEM of data from 3–5 cells. Unpaired 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.