Fischer, Thomas H. and Herting, Jonas and Mason, Fleur E. and Hartmann, Nico and Watanabe, Saera and Nikolaev, Viacheslav O. and Sprenger, Julia U. and Fan, Peidong and Yao, Lina and Popov, Aron-Frederik and Danner, Bernhard C. and Schoendube, Friedrich and Belardinelli, Luiz and Hasenfuss, Gerd and Maier, Lars S. and Sossalla, Samuel (2015) Late I-Na increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII. CARDIOVASCULAR RESEARCH, 107 (1). pp. 184-196. ISSN 0008-6363, 1755-3245
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Aims Enhanced cardiac late Na current (late I-Na) and increased sarcoplasmic reticulum (SR)-Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late I-Na and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and results In murine atrial CMs, SR-Ca2+-leak was increased by the late I-Na enhancer Anemonia sulcata toxin II (ATX-II). An inhibition of Ca2+/calmodulin-dependent protein kinase II (Autocamide-2-related inhibitory peptide), protein kinase A (H89), or late I-Na (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was not detected when either the Na+/Ca2+ exchanger was inhibited (KBR) or in CaMKIIdc-knockout mice. FRET measurements revealed increased cAMP levels upon ATX-II stimulation, which could be prevented by inhibition of adenylyl cyclases (ACs) 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA activation via an AC-dependent increase of cAMP levels. Western blots showed late I-Na-dependent hyperphosphorylation of CaMKII as well as PKA target sites at ryanodine receptor type-2 (-S2814 and -S2808) and phospholamban (-Thr17, -S16). Enhancement of late I-Na did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late I-Na activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased, whereas PKA inhibition reduced Ca2+-transient amplitude and load and additionally slowed Ca2+ elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late I-Na, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion Late I-Na exerts distinct effects on Ca2+ homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late I-Na represents a potential approach to attenuate CaMKII activation and decreases SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA system further increases the antiarrhythmic potential of late I-Na inhibition.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LATE SODIUM CURRENT; RAT VENTRICULAR MYOCYTES; RETICULUM CA2+ LEAK; PROTEIN-KINASE-II; TOXIN ATX-II; SARCOPLASMIC-RETICULUM; FIBRILLATION; RANOLAZINE; CURRENTS; PHOSPHOLAMBAN; Late Na current; Antiarrhythmic drugs; Atrial fibrillation; Protein kinases; SR-Ca2+-leak |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Jul 2019 08:19 |
| Last Modified: | 08 Jul 2019 08:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5236 |
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