期刊
CARDIOVASCULAR RESEARCH
卷 87, 期 4, 页码 609-617出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvq108
关键词
Calmodulin; Ryanodine receptor; Sarcoplasmic reticulum; Calcium; Heart failure
资金
- Ministry of Education in Japan [20390226, 20590868, 20591805, 19209030]
- Takeda Science Foundation
- National Heart, Lung and Blood Institutes [HL072841]
- Grants-in-Aid for Scientific Research [20390226, 20590868, 19209030, 20591805] Funding Source: KAKEN
Calmodulin (CaM) is well known to modulate the channel function of the cardiac ryanodine receptor (RyR2). However, the possible role of CaM on the aberrant Ca2+ release in diseased hearts remains unclear. In this study, we investigated the state of RyR2-bound CaM and channel dysfunctions in pacing-induced failing hearts. The characteristics of CaM binding to RyR2 and the role of CaM on the aberrant Ca2+ release were assessed in normal and failing canine hearts. The affinity of CaM binding to RyR2 was lower in failing sarcoplasmic reticulum (SR) than in normal SR. Addition of FK506, which dissociates FKBP12.6 from RyR2, to normal SR reduced the CaM-binding affinity. Dantrolene restored a normal level of the CaM-binding affinity in either FK506-treated (normal) SR or failing SR, suggesting that the defective inter-domain interaction between the N-terminal domain and the central domain of RyR2 (the therapeutic target of dantrolene) is involved in the reduction of the CaM-binding affinity in failing hearts. In saponin-permeabilized cardiomyocytes, the frequency of spontaneous Ca2+ sparks was much more increased in failing cardiomyocytes than in normal cardiomyocytes, whereas the addition of a high concentration of CaM attenuated the aberrant increase of Ca2+ sparks. The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca2+ release events in failing hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca2+ release in heart failure.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据