The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart - PubMed (original) (raw)
The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart
R P Xiao et al. J Physiol. 1997.
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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