| First Author | Okuda S | Year | 2018 |
| Journal | Biochem Biophys Res Commun | Volume | 496 |
| Issue | 4 | Pages | 1250-1256 |
| PubMed ID | 29402414 | Mgi Jnum | J:271671 |
| Mgi Id | MGI:6280044 | Doi | 10.1016/j.bbrc.2018.01.181 |
| Citation | Okuda S, et al. (2018) CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca(2+) release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun 496(4):1250-1256 |
| abstractText | AIMS: Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca(2+) release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). METHODS AND RESULTS: In TG cardiomyocytes, the Ca(2+) spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca(2+) transients (sCaTs) after cessation of a 1-5Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca(2+) sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca(2+) release is mediated by destabilized RyR2. CONCLUSIONS: In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca(2+)]i, causing aberrant Ca(2+) release leading to lethal arrhythmia. |
