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. 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.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
A M
AM
Cameron
J P
JP
Steiner
A J
AJ
Roskams
S M
SM
Ali
G V
GV
Ronnett
S H
SH
Snyder
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000302:isolation & purification / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured / Q000502:physiology; D002531:Cerebellum / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009124:Muscle Proteins / Q000302:isolation & purification / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000302:isolation & purification / Q000502:physiology*; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D011233:Precipitin Tests; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000302:isolation & purification / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel; D020123:Sirolimus; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins
D000935:Antifungal Agents; D015220:Calcium Channels; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009124:Muscle Proteins; D011090:Polyenes; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D015544:Inositol 1,4,5-Trisphosphate; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus