(Circulation. 2000;102:2131.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Altered Stoichiometry of FKBP12.6 Versus Ryanodine Receptor as a Cause of Abnormal Ca2+ Leak Through Ryanodine Receptor in Heart Failure
From the Second Department of Internal Medicine, Yamaguchi University School of Medicine, Yamaguchi, and the Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai (N.N., S.T., H.O.), Japan.
Correspondence to Masafumi Yano, MD, PhD, Second Department of Internal Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail yanoma{at}po.cc.yamaguchi-u.ac.jp
Background—In the pathogenesis of cardiac dysfunction in heart failure, a decrease in the activity of the sarcoplasmic reticulum (SR) Ca2+-ATPase is believed to be a major determinant. Here, we report a novel mechanism of cardiac dysfunction revealed by assessing the functional interaction of FK506–binding protein (FKBP12.6) with the cardiac ryanodine receptor (RyR) in a canine model of pacing-induced heart failure.
Methods and Results—SR vesicles were isolated from left
ventricular muscles (normal and heart failure). The
stoichiometry of FKBP12.6 per RyR was significantly decreased in
failing SR, as assessed by the ratio of the Bmax values for
[3H]dihydro-FK506 to those for
[3H]ryanodine binding. In normal SR, the molar ratio was
3.6 (
1 FKBP12.6 for each RyR monomer), whereas it was 1.6 in failing
SR. In normal SR, FK506 caused a dose-dependent Ca2+ leak
that showed a close parallelism with the conformational change in RyR.
In failing SR, a prominent Ca2+ leak was observed even in
the absence of FK506, and FK506 produced little or no further increase
in Ca2+ leak and only a slight conformational change in
RyR. The level of protein expression of FKBP12.6 was indeed found to be
significantly decreased in failing SR.
Conclusions—An abnormal Ca2+ leak through the RyR is present in heart failure, and this leak is presumably caused by a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR. This abnormal Ca2+ leak might possibly cause Ca2+ overload and consequent diastolic dysfunction, as well as systolic dysfunction.
Key Words: sarcoplasmic reticulum • heart failure • calcium • ion channels
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