FK506 and cyclic ADP-ribose can activate ryanodine receptors via an FKBP-independent mechanism in rat pancreatic acinar cells

Abstract

The immunosuppressant drug FK506 is knowm to modulate the ryanodine receptor (RyR) by dissociating FK506-binding protein (FKBP) from the RyR-FKBP complex in skeletal muscle. Cyclic ADP-ribose (cADPR) is also known to dissociate FKBP12.6, an isoform of FKBP, from cardiac-type RyRs. In the present study, the effects of FK506 and cADPR on Ca²⁺ release through FKBP-stripped RyRs were investigated in rat pancreatic acinar cells. After a steady state of ATP-dependent ⁴⁵Ca²⁺ uptake into the microsomal vesicles had been reached, cADPR- or FK506-induced ⁴⁵Ca²⁺ release from the vesicles was measured. Pretreatment of the vesicles with FK506 (3 μM) significantly increased cADPR (0.5-10 μM)-induced ⁴⁵Ca²⁺ release from the vesicles. The cADPR-induced ⁴⁵Ca²⁺ release in the presence of FK506 may not be due to the dissociation of FKBP, since it is thought that FKBP had been removed from the RyR by FK506 before the addition of cADPR. Pretreatment with cADPR (0.5 μM) significantly increased FK506 (0.1-10 μM)-induced ⁴⁵Ca²⁺ release from the vesicles. If the FKBP had been removed from the RyR by cADPR, the FK506-induced ⁴⁵Ca²⁺ release in the presence of cADPR may not be due to the dissociation of FKBP. The results suggest that an FKBP-independent mechanism is involved in FK506- or cADPR-induced Ca²⁺ release through RyRs in rat pancreatic acinar cells. [Jpn J Physiol 54 Suppl:S75 (2004)]