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

  title={Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux},
  author={Andrew M. Cameron and Joseph P. Steiner and A. Jane I. Roskams and Siraj M. Ali and Gabriele V. Ronnettt and Solomon H. Snyder},

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FKBP12 Binds the Inositol 1,4,5-Trisphosphate Receptor at Leucine-Proline (1400–1401) and Anchors Calcineurin to this FK506-like Domain*
It is demonstrated that FKBP12 binds the IP3R at residues 1400–1401, a leucyl-prolyl dipeptide epitope that structurally resembles FK506 that enables FK BP12 to interact with calcineurin, presumably to anchor the phosphatase toIP3R and modulate the receptor’s phosphorylation status.
Effects of FK506 on Ca2+ Release Channels (Review)
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  • 2008
Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect in T-lymphocytes and muscle cells, and it was found that FK506 itself induces Ca2+ release through RyRs in some tissues.
Calcineurin. Structure, function, and inhibition.
The X-ray structure of an FKPB12-FK506-calcineurin AB ternary complex reveals that FKBP12-FX506 binds in a hydophobic groove between the calcineur in A catalytic and the regulatory B subunit, in accord with biochemical and genetic studies on inhibitor action.
Cain, A Novel Physiologic Protein Inhibitor of Calcineurin*
Cain’s expression pattern in the brain closely resembles that of calcineurin, indicating a physiologic association between the two proteins, and the identification, molecular cloning, and functional characterization of a novel protein, cain, that interacts with and inhibits calcineURin.
Calcineurin regulates ryanodine receptor/Ca(2+)-release channels in rat heart.
Examination of physical and physiological interaction of protein phosphatase 2B, calcineurin, with the ryanodine receptor (RyR) in rat cardiac tissue and neonatal cardiomyocytes shows evidence that calcinesurin associated with the RyR could modulate Ca(2+) release in rat heart.
FK506 regulates Ca2+ release evoked by inositol 1,4,5‐trisphosphate independently of FK‐binding protein in endothelial cells
FK506 and rapamycin are modulators of FK‐binding proteins (FKBP) that are used to suppress immune function after organ and hematopoietic stem cell transplantations. The drugs share the unwanted
FK506 Regulates IP3 -evoked Ca2+ release independently of FKBP in Endothelial cells.
The hypertensive effects of the immunosuppressant drugs FK506 and rapamycin, while mediated by endothelial cells, do not appear to be exerted at documented cellular targets of the drugs on Ca2+ release and altered FKBP binding to IP3 and RyR.
FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells.
It is reported that force development in FKBP12.6-null mice, observed as a decrease in the concentration/tension relationship of isolated trachealis segments, is impaired, and this point to an important role of the FK BP 12.6/RyR2 complex in stochastic (spontaneous) and receptor-mediated Ca2+ release in smooth muscle.


Immunophilin FK506 binding protein associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux.
FKBP12 appears to be physiologically linked to IP3R, regulating its Ca2+ conductance, and is linked to the immunosuppressants FK506 and rapamycin, both of which are known to bind FKBP 12 with high affinity.
Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation
It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
Characterization of an Exchange Reaction between Soluble FKBP-12 and the FKBP·Ryanodine Receptor Complex
The studies show that the FKBP•RyR complex is in equilibrium with the cytosolic pool of FK BP (∼3 μM) and suggest that modulation of the CRC by FkBP is independent of PPIase activity.
FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin
It is reported that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner.
Charged surface residues of FKBP12 participate in formation of the FKBP12-FK506-calcineurin complex.
A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin
CYCLOSPORIN A and the newly discovered immunosuppressant, FK-506, are potent inhibitors of T cell activation1. In addition to their clinical importance in the prevention of allograft rejection,
Inositol 1,4,5‐Trisphosphate Receptor‐Mediated Ca2+ Signaling in the Brain
The structure and function of IP3R and its brain localization are focused on and its substantial role in brain physiology is not referred to, as it appears to be quantitatively distinct from Ca influx in neurons.
Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location.
It was found that overexpression of cyclophilin A or B or FKBP12 increased T-cell sensitivity to CsA and FK506, respectively, demonstrating that they are able to mediate the inhibitory effects of their respective immunosuppressants in vivo.