CALCINEURIN ASSOCIATED WITH THE INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR-FKBP12 COMPLEX MODULATES CA2+ FLUX

The immunosuppressant drug FK506 binds to the immunophilin protein FKBP12 and inhibits its prolyl isomerase activity. Immunosuppresive actions, however, are mediated via an FK506-FKBP12 inhibition of the Ca2+-activated phosphatase calcineurin. Physiologic cellular roles for FKBP12 have remained unclear. FKBP12 is physically associated with the RyR and IP(3)R Ca2+ channels in the absence of FK506, with added FK506 disrupting these complexes, Dissociation of FKBP12 results in alteration of channel Ca2+ conductance in both cases. We now report that calcineurin is physiologically associated with the IP(3)R-FKBP12 and RyR-FKBP12 receptor complexes and that this interaction can be disrupted by FK506 or rapamycin, Calcineurin anchored to the IP(3)R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca2+-sensitive regulation of IP3-mediated Ca2+ flux.