6 research outputs found

    Augmentation of SR Ca(2+) release by rapamycin and FK506 causes K(+)-channel activation and membrane hyperpolarization in bladder smooth muscle

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    1. The immunosuppressants rapamycin and FK506 are known to relax smooth muscle despite facilitating Ca(2+) release through ryanodine-receptors of the sarcoplasmic reticulum (SR). The apparent contradiction was studied in isolated guinea-pig urinary bladder myocytes. 2. Modulation of spontaneous SR Ca(2+) release was monitored by means of spontaneous transient outward currents (or STOCs) in isolated smooth muscle cells voltage-clamped to −20 mV. Rapamycin (10 μM, n=18) significantly increased amplitude (50±12%, mean±s.d.), life time (77±19%), and time integral of STOCs (113±22%), and it reduced the interval between STOCs (20±7%). FK506 (20 μM, n=24) increased amplitude (15±7%), life time (50±7%), time integral (104±26%). Cyclosporin A (20 μM, n=18) had no significant effects on STOCs. 3. The basal cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) measured by Indo1-fluorescence was insensitive to rapamycin or FK506. Pretreatment with rapamycin (20 μM, 2 min) did not impair the SR Ca(2+) load as can be concluded from caffeine-induced Ca(2+)-transients. 4. As it was expected from the enhanced STOC activity, the non-clamped membrane was hyperpolarized by rapamycin (15±2 mV) or by FK506 (15±3 mV). 5. The data are consistent with the idea that rapamycin and FK506 augment spontaneous SR Ca(2+) release by removal of FK-binding proteins from the RyR-complex. Smooth muscle relaxation is interpreted as negative Ca(2+) feedback: augmented Ca(2+) activation of STOCs induces membrane hyperpolarization that reduces Ca(2+) influx through voltage gated channels

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