Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antifungal Agents / pharmacology
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Calcineurin
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Calcium / metabolism*
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Calcium Channels / isolation & purification
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Calcium Channels / metabolism*
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Calmodulin-Binding Proteins / isolation & purification
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Calmodulin-Binding Proteins / metabolism
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Calmodulin-Binding Proteins / physiology*
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Carrier Proteins / metabolism*
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Cells, Cultured / physiology
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Cerebellum / cytology
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DNA-Binding Proteins / metabolism*
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Heat-Shock Proteins / metabolism*
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Immunosuppressive Agents / metabolism
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Inositol 1,4,5-Trisphosphate / metabolism*
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Inositol 1,4,5-Trisphosphate Receptors
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Muscle Proteins / isolation & purification
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Muscle Proteins / metabolism
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Phosphoprotein Phosphatases / isolation & purification
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Phosphoprotein Phosphatases / physiology*
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Phosphorylation
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Polyenes / pharmacology
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Precipitin Tests
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Rats
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Receptors, Cytoplasmic and Nuclear / isolation & purification
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Ryanodine Receptor Calcium Release Channel
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Sirolimus
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Tacrolimus / metabolism
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Tacrolimus Binding Proteins
Substances
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Antifungal Agents
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Calcium Channels
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Calmodulin-Binding Proteins
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Carrier Proteins
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DNA-Binding Proteins
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Heat-Shock Proteins
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Immunosuppressive Agents
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Inositol 1,4,5-Trisphosphate Receptors
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Muscle Proteins
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Polyenes
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Receptors, Cytoplasmic and Nuclear
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Ryanodine Receptor Calcium Release Channel
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Inositol 1,4,5-Trisphosphate
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Calcineurin
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Phosphoprotein Phosphatases
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Tacrolimus Binding Proteins
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Calcium
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Sirolimus
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Tacrolimus