Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca2+ release in heart failure

doi:10.1016/S0008-6363(00)00191-7

Cardiovascular Research 2000 48(2):323-331; doi:10.1016/S0008-6363(00)00191-7
© 2000 by European Society of Cardiology

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Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca²⁺ release in heart failure

Kaoru Ono, Masafumi Yano, Tomoko Ohkusa, Masateru Kohno, Takayuki Hisaoka, Taketo Tanigawa, Shigeki Kobayashi, Michihuro Kohno and Masunori Matsuzaki^*

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⁺ releasefunction of the sarcoplasmic reticulum (SR) in heart failure.We assessed whether the alteration in this function in heartfailure is related to a change in the role of FK binding protein(FKBP), which is tightly coupled with the cardiac ryanodinereceptor (RyR) and recently identified as a modulatory proteinacting to stabilize the gating function of RyR. Methods: SRvesicles were isolated from dog LV muscles [normal (N), n =6; heart failure induced by 3-weeks pacing (HF), n = 6]. Thetime course of the SR Ca²⁺ release was continuously monitoredusing 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 dissociatesit from RyR, decreased the polylysine-induced enhancement of[³H]ryanodine-binding by 38% in N (P<0.05) but it had noeffect in HF. In HF, the rate constant for the polylysine-inducedCa²⁺ release from the SR was 61% smaller than in N. FK506 decreasedthe rate constant for the polylysine-induced Ca²⁺ release by67% in N (P<0.05) but had no effect in HF. The [³H]dihydro-FK506-bindingassay revealed that the number (B_max) of FKBPs was decreasedby 83% in HF (P<0.05), while the K_d value was unchanged.FK506 did not significantly change SR Ca^2+.-ATPase activityin either N or HF. Conclusions: In HF, the number of FKBPs showeda tremendous decrease; this may underlie the RyR-channel instabilityand the impairment of the Ca²⁺ release function of RyR seenin 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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