Cyclic ADP-ribose binds to FK506-binding protein 12.6 to Release Ca²⁺ from islet microsomes

Cyclic ADP-ribose (cADPR) is a second messenger for Ca²⁺ mobilization via the ryanodine receptor (RyR) from islet microsomes for insulin secretion (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373). In the present study, FK506, an immunosuppressant that prolongs allograft survival, as well as cADPR were found to induce the release of Ca²⁺ from islet microsomes. After islet microsomes were treated with FK506, the Ca²⁺ release by cADPR from microsomes was reduced. cADPR as well as FK506 bound to FK506-binding protein 12.6 (FKBP12.6), which we also found occurs naturally in islet microsomes. When islet microsomes were treated with cADPR, FKBP12.6 dissociated from the microsomes and moved to the supernatant, releasing Ca²⁺ from the intracellular stores. The microsomes that were then devoid of FKBP12.6 did not show Ca²⁺ release by cADPR. These results strongly suggest that cADPR may be the ligand for FKBP12.6 in islet RyR and that the binding of cADPR to FKBP12.6 frees the RyR from FKBP12.6, causing it to release Ca²⁺.