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The immunophilin FK506‐binding protein modulates Ca2+ release channel closure in rat heart.
Author(s) -
Xiao R P,
Valdivia H H,
Bogdanov K,
Valdivia C,
Lakatta E G,
Cheng H
Publication year - 1997
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.1997.sp022025
Subject(s) - ryanodine receptor , fkbp , biophysics , depolarization , chemistry , endoplasmic reticulum , electrophysiology , time constant , patch clamp , intracellular , myocyte , channel blocker , medicine , calcium , endocrinology , receptor , biochemistry , biology , engineering , electrical engineering , organic chemistry
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.