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

Background-In the pathogenesis of cardiac dysfunction in heart failure, a d ecrease in the activity of the sarcoplasmic reticulum (SR) Ca2+-ATPase is b elieved to be a major determinant. Here, we report a novel mechanism of car diac dysfunction revealed by assessing the functional interaction of FK506- binding protein (FK8P12.6) with the cardiac ryanodine receptor (RyR) in a c anine 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 sign ificantly decreased in failing SR, as assessed by the ratio of the B-max va lues ;for [H-3]dihydro-FK506 to those for [H-3]ryanodine binding, In normal SR, the molar ratio was 3.6 (approximate to1 FKBP12.6 for each RyR monomer ), whereas it was 1.6 in failing SR. In normal SR, FK506 caused a dose-depe ndent Ca2+ leak that showed a close parallelism with the conformational cha nge in RyR. In failing SR, a prominent Ca2+ leak was observed even in the a bsence of FK506, and FK506 produced little or no further increase in Ca2+ l eak and only a slight conformational change in RyR, The level of protein ex pression of FKBP12.6 was indeed found to be significantly decreased in fail ing SR. Conclusions-An abnormal Ca2+ leak through the RyR is present in heart failu re, and this leak is presumably caused by a partial loss of RyR-bound FKBP1 2.6 and the resultant conformational change in RyR, This abnormal Ca2+ leak might possibly cause Ca2+ overload and consequent diastolic dysfunction, a s well as systolic dysfunction.