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. 1997 Apr 15;500(Pt 2):343–354. doi: 10.1113/jphysiol.1997.sp022025

The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart.

R P Xiao 1, H H Valdivia 1, K Bogdanov 1, C Valdivia 1, E G Lakatta 1, H Cheng 1
PMCID: PMC1159388  PMID: 9147322

Abstract

1. The nature of the signal that terminates the release of Ca2+ from the cardiac sarcoplasmic reticulum has remained elusive. This study was intended to examine whether FK506-binding protein (FKBP), which is tightly associated to the ryanodine receptor (RyR)/Ca2+ release channel, plays a role in the termination of Ca(2+)-induced Ca2+ release (CICR) in heart. 2. Confocal microscopy and the Ca2+ indicator fluo-3 were used to visualize the elementary release events, i.e. 'Ca2+ sparks' in rat ventricular myocytes under resting or voltage-clamped conditions. Additionally, electrophysiological single-channel recordings, at constant [Ca2+] or during [Ca2+] steps produced by photorelease of caged Ca2+, were obtained from rat cardiac RyRs incorporated in planar lipid bilayers. 3. Inhibition of FKBP by the immunosuppressants FK506 or rapamycin increased the duration of spontaneous or depolarization-evoked Ca2+ sparks 6- to 7-fold. In addition, Ca2+ sparks were seen with two-level amplitudes, corresponding to full and half normal spark amplitude. 4. FK506 potentiated and prolonged electrically stimulated [Ca2+]i transients and contractions, but did not affect the amplitude and kinetics of the L-type Ca2+ channel current. 5. In planar lipid bilayers, FK506 (15 microM) prolonged approximately 7-fold the mean open lifetime of reconstituted single RyRs, induced the appearance of long-lasting subconductance states, and markedly slowed the spontaneous decay of RyR activity elicited by fast and sustained Ca2+ stimuli. The time constant of the spontaneous decay of activity increased from 1.8 s in control to > or = 20 s in the presence of FK506. 6. We conclude that FKBP may afford an intrinsic mechanism to terminate RyR openings and it may thus exert a negative feedback on CICR in heart cells.

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Selected References

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