Modification of sarcoplasmic reticulum (SR) Ca2+ release by FK506 induces defective excitation-contraction coupling only when SR Ca2+ recycling is disturbed.
This study examined whether the effects of FK506-binding protein dissociation from sarcoplasmic reticulum (SR) Ca(2+) release channels on excitation-contraction (EC) coupling changed when SR Ca(2+) reuptake and (or) the trans-sarcolemmal Ca(2+) extrusion were altered. The steady-state twitch Ca(2+) transient (CaT), cell shortening, post-rest caffeine-induced CaT, and Ca(2+) sparks were measured in rat ventricular myocytes using laser-scanning confocal microscopy. In the normal condition, 50 micromol FK506/L significantly increased steady-state CaT, cell shortening, and post-rest caffeine-induced CaT. When the cells were solely perfused with thapsigargin, FK506 did not reduce any of the states, but when low [Ca(2+)](0) (0.1 mmol/L) was perfused additionally, FK506 reduced CaT and cell shortening, and accelerated the reduction of post-rest caffeine-induced CaT. FK506 significantly increased Ca(2+) spark frequency in the normal condition, whereas it mainly prolonged duration of individual Ca(2+) sparks under the combination of thapsigargin and low [Ca(2+)](0) perfusion. Modification of SR Ca(2+) release by FK506 impaired EC coupling only when released Ca(2+) could not be taken back into the SR and was readily extruded to the extracellular space. Our findings could partly explain the controversy regarding the contribution of FK506-binding protein dissociation to defective EC coupling.
Yoshihara
Shu
S
Division of Cardiology, Internal Medicine III, Hamamatsu University of School of Medicine, Japan.
Satoh
Hiroshi
H
Saotome
Masao
M
Katoh
Hideki
H
Terada
Hajime
H
Watanabe
Hiroshi
H
Hayashi
Hideharu
H
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium; D016559:Tacrolimus