Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits.
Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits.
复制标题
DOI：
10.1172/jci.insight.143092
复制
发表时间：
2021-08-09
期刊：
影响因子：
8
通讯作者：
Silva JR
中科院分区：
文献类型：
--
作者：
Zhu W;Wang W;Angsutararux P;Mellor RL;Isom LL;Nerbonne JM;Silva JR
天然心肌电压门控钠（NaV）通道在包含成孔（α）亚基和多种辅助蛋白的大分子复合物中起作用。在此，我们研究了辅助NaVβ1和NaVβ3亚基对2种众所周知的Ib类抗心律失常药利多卡因和雷诺嗪对哺乳动物心脏中表达的主要NaV通道α亚基NaV 1.5的功能效应的影响。我们发现，这两种药物稳定了NaV1.5中结构域III（DIII-VSD）电压传感器的活化构象。在NaVβ1存在下，利多卡因对DIII-VSD的作用增强，而雷诺嗪的作用消失。使主要的Ib类药物结合位点F1760突变，影响但不消除NaVβ1/β3对药物阻滞的调节。成年小鼠心室肌细胞的记录表明，Scn 1b（NaVβ1）的缺失对利多卡因和雷诺嗪的效力有不同的影响。体内实验显示WT和Scn 1b-null动物腹腔注射雷诺嗪或利多卡因后的ECG反应不同，表明NaVβ1在整个心脏水平调节药物反应。在人类心脏中，我们发现心房中的SCN 1B转录本表达是心室的3倍，这种差异与遗传性或获得性心血管疾病相结合，可能会显著影响患者对Ib类抗心律失常治疗的反应。
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.
登录
查看更多内容
影响因子：
4.6
作者：
Johnson EK;Matkovich SJ;Nerbonne JM
通讯作者：
Nerbonne JM
影响因子：
5.5
作者：
Brunet, S;Aimond, F;Nerbonne, JM
通讯作者：
Nerbonne, JM
DOI：
10.1085/jgp.201611678
发表时间：
2017-03-06
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hsu EJ;Zhu W;Schubert AR;Voelker T;Varga Z;Silva JR
通讯作者：
Silva JR
影响因子：
56.9
作者：
ISOM, LL;DEJONGH, KS;CATTERALL, WA
通讯作者：
CATTERALL, WA
影响因子：
4.6
作者：
Kittleson, MM;Minhas, KM;Hare, JM
通讯作者：
Hare, JM