Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux

• Published in: Cell 1995-11, Vol.83 (3), p.463-472
• Main Authors: Cameron, A M, Steiner, J P, Roskams, A J, Ali, S M, Ronnett, G V, Snyder, S H
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - pharmacology; Calcineurin; Calcium - metabolism; Calcium Channels - isolation & purification; Calcium Channels - metabolism; Calmodulin-Binding Proteins - isolation & purification; Calmodulin-Binding Proteins - metabolism; Calmodulin-Binding Proteins - physiology; Carrier Proteins - metabolism; Cells, Cultured - physiology; Cerebellum - cytology; DNA-Binding Proteins - metabolism; Heat-Shock Proteins - metabolism; Immunosuppressive Agents - metabolism; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-Trisphosphate Receptors; Muscle Proteins - isolation & purification; Muscle Proteins - metabolism; Phosphoprotein Phosphatases - isolation & purification; Phosphoprotein Phosphatases - physiology; Phosphorylation; Polyenes - pharmacology; Precipitin Tests; Rats; Receptors, Cytoplasmic and Nuclear - isolation & purification; Receptors, Cytoplasmic and Nuclear - metabolism; Ryanodine Receptor Calcium Release Channel; Sirolimus; Tacrolimus - metabolism; Tacrolimus Binding Proteins
• ISSN: 0092-8674
• DOI: 10.1016/0092-8674(95)90124-8

The immunosuppressant drug FK506 binds to the immunophilin protein FKBP12 and inhibits its prolyl isomerase activity. Immunosuppressive actions, however, are mediated via an FK506-FKBP12 inhibition of the Ca(2+)-activated phosphatase calcineurin. Physiologic cellular roles for FKBP12 have remained unclear. FKBP12 is physically associated with the RyR and IP3R 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 IP3R-FKBP12 and RyR-FKBP12 receptor complexes and that this interaction can be disrupted by FK506 or rapamycin. Calcineurin anchored to the IP3R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca(2+)-sensitive regulation of IP3-mediated Ca2+ flux.