Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca2+ leak through ryanodine receptor in heart failure

Masafumi Yano, Kaoru Ono, Tomoko Ohkusa, Masae Suetsugu, Masateru Kohno, Takayuki Hisaoka, Shigeki Kobayashi, Yuji Hisamatsu, Takeshi Yamamoto, Michihiro Kohno, Naoya Noguchi, Shin Takasawa, Hiroshi Okamoto, Masunori Matsuzaki

Research output: Contribution to journalArticlepeer-review

186 Citations (Scopus)

Abstract

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 B(max) 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.

Original languageEnglish
Pages (from-to)2131-2136
Number of pages6
JournalCirculation
Volume102
Issue number17
DOIs
Publication statusPublished - 2000 Oct 24

Keywords

  • Calcium
  • Heart failure
  • Ion channels
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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