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Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux
A M Cameron1, J P Steiner, A J Roskams
1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
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.
Insights
The immunosuppressant FK506 drug disrupts FKBP12 protein complexes with calcium channels. This reveals FKBP12
Area of Science:
- Cellular Biology
- Immunology
- Pharmacology
Background:
- The immunosuppressant drug FK506 (tacrolimus) targets the immunophilin FKBP12.
- FKBP12 is known to associate with calcium channels (RyR and IP3R) and calcineurin, a phosphatase involved in immunosuppression.
- The precise physiological role of FKBP12 in regulating these interactions remained unclear.
Purpose of the Study:
- To investigate the physiological association between FKBP12, calcium channels, and calcineurin.
- To determine how FK506 and rapamycin affect these molecular complexes.
- To elucidate the role of calcineurin in regulating IP3R function via FKBP12.
Main Methods:
- Co-immunoprecipitation assays to detect protein-protein interactions.
- Treatment with FK506 and rapamycin to disrupt molecular complexes.
- Analysis of calcium channel conductance and receptor phosphorylation.
Main Results:
- FKBP12 is constitutively associated with RyR and IP3R calcium channels.
- FK506 and rapamycin disrupt the FKBP12 association with these channels.
- Calcineurin physiologically interacts with FKBP12-associated IP3R and RyR complexes.
- Calcineurin binding to IP3R via FKBP12 regulates receptor phosphorylation and IP3-mediated calcium flux.
Conclusions:
- FKBP12 acts as a scaffold, bringing calcineurin into proximity with IP3R and RyR calcium channels.
- FK506 and rapamycin interfere with this scaffold, altering calcium channel regulation.
- This interaction provides a mechanism for dynamic, calcium-sensitive regulation of cellular calcium signaling.