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

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.

Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death

“…As a small soluble protein, GAPDH might serve as a chaperone, translocating proteins between intracellular sites. A similar chaperone function has been reported for the abundant, small molecular immunophilin protein FKBP12, which serves as a scaffold, linking large proteins such as the inositol-1,4,5-trisphophate receptor and calcineurin (40). AKAP (A-kinase anchoring protein) similarly links cAMP-dependent protein kinase and calcineurin (41).…”

TGF-β1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes

“…This is consistent with our observations that T cells, but not B cells, are the primary effectors in inflammatory disease, since Tgfb1 Ϫ/Ϫ athymic nude mice also live much longer than immunocompetent Tgfb1 Ϫ/Ϫ mice. FK506-binding protein-12 (FKBP12) is known to be released from association with TGF-␤ receptor I upon ligand binding (45) and to recruit calcineurin to the inositol trisphosphate receptor complex (46), where together they are required for fully functional inositol trisphosphate receptor activity (47,48). That FKBP12 can function in TGF-␤ signaling is strongly suggested by the facts that Fkbp12 knockout mice have cardiomyocyte defects that involve abnormal Ca 2ϩ channel function (49), and Fkbp12 and Tgfb2 knockout mice have similar morphological defects in the developing heart (49,50).…”

Selective inhibition of calcineurin-NFAT signaling by blocking protein–protein interaction with small organic molecules

“…The conventional method of blocking calcineurin-NFAT signaling is to apply the immunosuppressive compounds cyclosporin A (CsA) and FK506, which, in the form of CsA-cyclophilin or FK506-FKBP12 complexes, inhibit the enzymatic activity of calcineurin toward all its physiological substrates (33). However, calcineurin employs a range of targeting mechanisms (1,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) that offer conceptually novel possibilities for disrupting calcineurinsubstrate signaling. In particular, a protein-protein interaction of calcineurin with NFAT-family proteins controls the efficiency of NFAT dephosphorylation in vitro and in cells (1,16,44,45).…”