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Effects of the immunosuppressant FK506 on intracellular Ca²⁺ release and Ca²⁺ accumulation mechanisms

Geert Bultynck, Patrick De Smet, A. Frederik Weidema, Mark Ver Heyen, Karlien Maes, Geert Callewaert, Ludwig Missiaen, Jan B. Parys and Humbert De Smedt

1. The immunophilin FKBP12 associates with intracellular Ca²⁺ channels and this interaction can be disrupted by the immunosuppressant FK506. We have investigated the effect of FK506 on Ca²⁺ release and Ca²⁺ uptake in permeabilized cell types.

2. Changes in medium free [Ca²⁺] were detected by the fluorescent Ca²⁺ indicator fluo-3 in digitonin-permeabilized SH-SY5Y human neuroblastoma cells, DT40 and R23-11 (i.e. triple inositol 1,4,5-trisphosphate (IP₃) receptor knockout cells) chicken B lymphocytes and differentiated and undifferentiated BC₃H1 skeletal muscle cells. ⁴⁵Ca²⁺ fluxes were studied in saponin-permeabilized A7r5 rat smooth muscle cells.

3. Addition of FK506 to permeabilized SH-SY5Y cells led to a sustained elevation of the medium [Ca²⁺] corresponding to ~30 % of the Ca²⁺ ionophore A23187-induced [Ca²⁺] rise. This rise in [Ca²⁺] was not dependent on mitochondrial activity.

4. This FK506-induced [Ca²⁺] rise was related to the inhibition of the sarcoplasmic/endoplasmic reticulum Ca²⁺-Mg²⁺-ATPase (SERCA) Ca²⁺ pump. Oxalate-facilitated ⁴⁵Ca²⁺ uptake in SH-SY5Y microsomes was inhibited by FK506 with an IC₅₀ of 19 µM.

5. The inhibition of the SERCA Ca²⁺ pump was not specific since several macrocyclic lactone compounds (ivermectin > FK506, ascomycin and rapamycin) were able to inhibit Ca²⁺ uptake activity.

6. FK506 (10 µM) did not affect IP₃-induced Ca²⁺ release in permeabilized SH-SY5Y and A7r5 cells, but enhanced caffeine-induced Ca²⁺ release via the ryanodine receptor (RyR) in differentiated BC₃H1 cells.

7. In conclusion, FK506 inhibited active Ca²⁺ uptake by the SERCA Ca²⁺ pump; in addition, FK506 enhanced intracellular Ca²⁺ release through the RyR, but it had no direct effect on IP₃-induced Ca²⁺ release.

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