NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling

Tarasov M., Struckman H. L., Olgar Y., Miller A., Demirtaş M., Bogdanov V., ...Daha Fazla

JOURNAL OF CLINICAL INVESTIGATION, cilt.1, ss.1-34, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1172/jci152071
  • Dergi Adı: JOURNAL OF CLINICAL INVESTIGATION
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, CINAHL, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Sayfa Sayıları: ss.1-34
  • Bursa Uludağ Üniversitesi Adresli: Evet

Özet

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCC). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels. Here, we provide evidence implicating NaV dysregulation within transverse (T)-tubules in D96V-CaM-associated arrhythmias. D96V-CaM induces pro-arrhythmic late Na+ current (INa) by impairing inactivation of NaV1.6, but not the predominant cardiac NaV isoform, NaV1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super resolution microscopy revealed close proximity of NaV1.6 and RyR2 within T-tubules. NaV1.6 density within these regions increased in cD96V relative to WT. Consistent with NaV1.6 dysregulation by D96V-CaM in these regions, we observed increased late NaV activity in Ttubules. The resulting late INa promoted aberrant Ca2+ release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia (VT) in vivo. Cardiac-specific NaV1.6 knockout protected cD96V mice from increased T-tubular late NaV activity, and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promotes arrhythmias by dysregulating LTCC and NaV1.6 within T-tubules and thereby, facilitating aberrant Ca2+ release.