© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca2+ release in heart failure
Second Department of Internal Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan
* Corresponding author. Tel.: +81-836-22-2248; fax: +81-836-22-2246 masunori{at}po.cc.yamaguchi-u.ac.jp
Objective: Little information is available as to the Ca2+ release function of the sarcoplasmic reticulum (SR) in heart failure. We assessed whether the alteration in this function in heart failure is related to a change in the role of FK binding protein (FKBP), which is tightly coupled with the cardiac ryanodine receptor (RyR) and recently identified as a modulatory protein acting to stabilize the gating function of RyR. Methods: SR vesicles were isolated from dog LV muscles [normal (N), n = 6; heart failure induced by 3-weeks pacing (HF), n = 6]. The time course of the SR Ca2+ release was continuously monitored using a stopped-flow apparatus, and [3H]ryanodine-binding and [3H]dihydro-FK506-binding assays were also performed. Results: FK506, which specifically binds to FKBP12.6 and dissociates it from RyR, decreased the polylysine-induced enhancement of [3H]ryanodine-binding by 38% in N (P<0.05) but it had no effect in HF. In HF, the rate constant for the polylysine-induced Ca2+ release from the SR was 61% smaller than in N. FK506 decreased the rate constant for the polylysine-induced Ca2+ release by 67% in N (P<0.05) but had no effect in HF. The [3H]dihydro-FK506-binding assay revealed that the number (Bmax) of FKBPs was decreased by 83% in HF (P<0.05), while the Kd value was unchanged. FK506 did not significantly change SR Ca2+.-ATPase activity in either N or HF. Conclusions: In HF, the number of FKBPs showed a tremendous decrease; this may underlie the RyR-channel instability and the impairment of the Ca2+ release function of RyR seen in the failing heart.
KEYWORDS SR, sarcoplasmic reticulum; RyR, ryanodine receptor; E–C coupling, excitation–contraction coupling; FKBP, FK binding protein; PMSF, phenylmethanesulfonyl fluoride; MES, 2-(N-morpholino)ethanesulfonic acid; MOPS, 3-[N-morpholino]propanesulfonic acid; EGTA, ethylene glycol bis(β-aminoethyl ether)N,N,N',N'-tetraacetic acid; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate; DTT, dithiothreitol; BSA, bovine serum albumin
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