| Autor: |
Abrams J; Division of Cardiology, Department of Medicine., Roybal D; Department of Pharmacology, and., Chakouri N; Department of Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA., Katchman AN; Division of Cardiology, Department of Medicine., Weinberg R; Division of Cardiology, Department of Medicine., Yang L; Division of Cardiology, Department of Medicine., Chen BX; Division of Cardiology, Department of Medicine., Zakharov SI; Division of Cardiology, Department of Medicine., Hennessey JA; Division of Cardiology, Department of Medicine., Avula UMR; Division of Cardiology, Department of Medicine., Diaz J; Department of Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA., Wang C; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA., Wan EY; Division of Cardiology, Department of Medicine., Pitt GS; Cardiovascular Research Institute, Weill Cornell Medical College, New York, New York, USA., Ben-Johny M; Department of Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA., Marx SO; Division of Cardiology, Department of Medicine.; Department of Pharmacology, and. |
| Abstrakt: |
The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current. |
