Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca(2+) release in heart failure.
OBJECTIVE
Little information is available as to the Ca(2+) 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 Ca(2+) 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 Ca(2+) release from the SR was 61% smaller than in N. FK506 decreased the rate constant for the polylysine-induced Ca(2+) release by 67% in N (P<0.05) but had no effect in HF. The [3H]dihydro-FK506-binding assay revealed that the number (B(max)) of FKBPs was decreased by 83% in HF (P<0.05), while the K(d) value was unchanged. FK506 did not significantly change SR Ca(2+.)-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 Ca(2+) release function of RyR seen in the failing heart.
Ono
K
K
Second Department of Internal Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, 755-8505, Yamaguchi, Japan.
Yano
M
M
Ohkusa
T
T
Kohno
M
M
Hisaoka
T
T
Tanigawa
T
T
Kobayashi
S
S
Kohno
M
M
Matsuzaki
M
M
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D008297:Male; D011107:Polylysine / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012433:Ryanodine / Q000737:chemistry / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D016559:Tacrolimus / Q000737:chemistry / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D011107:Polylysine; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium; D016559:Tacrolimus