| First Author | Chakouri N | Year | 2022 |
| Journal | Nat Cardiovasc Res | Volume | 1 |
| Issue | 5 | Pages | 1-13 |
| PubMed ID | 35662881 | Mgi Jnum | J:359225 |
| Mgi Id | MGI:7782722 | Doi | 10.1038/s44161-022-00060-6 |
| Citation | Chakouri N, et al. (2022) Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current. Nat Cardiovasc Res 1(5):1-13 |
| abstractText | Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of Na(V)1.5 inactivation results in a small persistent Na influx known as late Na current (I (Na,L)), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. Here, using low-noise multi-channel recordings in heterologous systems, LQTS3 patient-derived iPSCs cardiomyocytes, and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1-4) tune pathogenic I (Na,L) in an isoform-specific manner. This scheme suggests a complex orchestration of I (Na,L) in cardiomyocytes that may contribute to variable disease expressivity of Na(V)1.5 channelopathies. We further leverage these observations to engineer a peptide-inhibitor of I (Na,L) with a higher efficacy as compared to a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I (Na,L) in pathophysiology and outline potential therapeutic avenues. |
