CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy.

Abstract

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 Ca2+ 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 Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). 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 Ca2+ transients (sCaTs) after cessation of a 1-5 Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ 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 [Ca2+]i, causing aberrant Ca2+ release leading to lethal arrhythmia.

• Authors: Shinichi Okuda, Yoko Sufu-Shimizu, Takayoshi Kato, Masakazu Fukuda, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Sachio Morimoto, Masafumi Yano
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 496 Issue 4 Pg. 1250-1256 (02 19 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29402414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Troponin T
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium

Topics

• Animals
• Arrhythmias, Cardiac (etiology, physiopathology)
• Calcium (metabolism)
• Calcium Signaling
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cardiomyopathy, Hypertrophic, Familial (complications, physiopathology)
• Cells, Cultured
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (metabolism)
• Phosphorylation
• Sarcoplasmic Reticulum (metabolism)
• Troponin T (metabolism)