Calcineurin


2007 Copy

A protein phosphatase which is involved in the activation of IL-2 transcription; IL-2 stimulated the T-Cell response. Calcineurin is inhibited by immuosuppressive drugs such as cyclosporine and FK506(tacrolimus).  See Pallen, C.J. and Wang, J.H., A multifunctional calmodulin-stimulated phosphatase, Arch.Biochem.Biophys. 237, 281-291, 1985; Klee, C.B., Draetta, G.F., and Hubbard, M.J., Calcineurin, Adv.Enzymol.Relat.Areas Mol.Biol. 61, 149-200, 1988; Siekierka, J.J. and Sigal, N.H., FK-506 and cyclosporine A: immunosuppressive mechanism of action and beyond, Curr.Opin.Immunol. 4, 484-552, 1992;Groenendyk, J., Lynch, J., and Michalak, M., Calreticulin, Ca2+, and calcineurin – signaling from the endoplasmic reticulum, Mol.Cells 30, 383-389, 2004; Michel, R.N., Dunn, S.E. and Chin, E.R., Calcineurin and skeletal muscle growth, Proc.Nutr.Soc. 63, 341-349, 2004; Im, S.H. and Rao, A., Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling, Mol.Cells 16, 1-9, 2004; Bandyopadhyay, J., Lee, J. and Bandopadhyay, A., Regulation of calcineurin, a calcium/calmodulin-dependent protein phosphatase in C.elegans, Mol.Cells 18, 10-16, 2004; Taylor, A.L., Watson, C.J., and Bradley, J.A., Immunosuppresive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy, Crit.Rev.Oncol.Hematol. 56, 23-46, 2005; Crespo-Leiro, M.G., Calcineurin inhibitors in heart transplantation, Transplant.Proc.37, 4018-4020, 2005,   

2018 Draft for second edition of Compendium


Calcineurin is a protein phosphatase consisting to two dissimilar subunits (Guerini, D., Calcineurin: Not just a simple protein phosphatase, Biochem.Biophys.Res.Commun. 235, 271-275, 1997; Rusnak, F. and Mertz, F., Calcineurin: Form and function, Physiol.Rev. 80, 1483-1521, 2000).  Early studies refered to calcineurin as protein phosphatase 2B (Stewart, A.A., Ingebritsen, T.S., and Cohen, P., The protein phosphatases involved in cellular regulation. 5. Purification and properties of a Ca2+/calmodulin-dependent protein phosphatase (2B) from rabbit skeletal muscle, Eur.J.Biochem. 132, 289-295, 1983). The heterodimer consists of a 57-59 kDa catalytic subunit (CnA) and a 19-20 kDa regulatory subunit (CnB).  Calcineurin is “activated by the binding of Ca2+/calmodulin (Yang, S.D., Tallant, E.A., and Cheung, W.Y., Calcineurin is a calmodulin-dependent protein phosphatase, Biochem.Biophys.Res.Commun. 106, 1419-1425, 1982).   The term calcineurin was advanced in 1979 (Klee, C.B., Crouch, T.H., and Krinks, M.H., Calcineurin: A calcium- and calmodulin-binding protein of the nervous system, Proc.Natl.Acad.Sci. USA 76, 6270-6275, 1979) to describe a protein isolated in 1978 as an inhibitor of 3’,5’-nucleotide phosphodiesterase (Klee, C.B., and Krinks, M.H., Purification of cyclic 3’,5’-nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to Sepharose, Biochemistry 17, 120-126, 1978).  Early work had shown that cyclosporin in combination with an immunophilin(Friedman, J. and Weissman, I., Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA, Cell 66, 799-806, 1991) inhibited T-cell activation(Thomson, A.W., Woo, J., and Coooper,M., Mode of action of immunosuppression drugs with particular reference to the molecular basis of macrolide-induced immunosuppression,  in The Molecular Biology of Immunosuppression, ed. A.W. Thomson, Chapter 8, pps. 153-179, John Wiley & Sons, Chichester, United Kingdom, 1992) in its role as an immunosuppression agent.  It shortly shown that the action of cyclosporin and FK-506 as immunosuppression drugs were mediated through direction action on calcineurin (Liu, J. Farmer, J.D.,Jr., Lane, W.B., et al., Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes, Cell 66, 807-815, 1991). Subsequent work has shown that calcineurin, in response to increased intracellular calcium ion, is a critical mediator of T-cell activation (Crabtree, C.B., Calcium, calcineurin, and the control of transcription, J.Biol.Chem. 275, 2313-2316, 2001; Cristillo, A.D. and Bierer, B.E., Immunophilins and the immunophilin-binding agents, in Clinical Immunology Prnciples and Practice, 2nd edn., ed.  Rich, R.R., Fleisher, T.A., Shearer, W.T., Kotzin, B.L, and Schroeder, H.W., Jr., Section 111, Mosby, London, United Kingdom, 2001; Hogan, P.G., Calcium-NFAT transcriptional signalling in T cell activation and T cell exhaustion, Cell Calcium 63, 66-60, 2017). While there has  been much emphasis on the role of calcineurin in T-cells,  there is considerable interest in the role of calcineurin in nervous tissue (Woolfrey, K.M. and Dell’Acqua, M.L., Coordination of protein phosphorylation and dephosphorylation in synaptic plasticity, J.Biol.Chem. 290, 28604-28612, 2015) and glucose metabolism (Chalckera, H.A., Kudva, Y., and Kaplan, B., Calcineurin inhibitors: Pharmacologic mechanism impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, Clin.Pharmacol.Ther. 101, 114-120, 2017).