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Physiological Reviews, Vol. 80, No. 4, October 2000, pp. 1483-1521
Copyright ©2000 by the American Physiological Society
Section of Hematology Research and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; and Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts
Rusnak, Frank and
Pamela Mertz.
Calcineurin: Form and Function. Physiol. Rev. 80: 1483-1521, 2000.
Calcineurin is
a eukaryotic Ca2+- and calmodulin-dependent
serine/threonine protein phosphatase. It is a heterodimeric protein consisting of a catalytic subunit calcineurin A, which contains an
active site dinuclear metal center, and a tightly associated, myristoylated, Ca2+-binding subunit, calcineurin B. The
primary sequence of both subunits and heterodimeric quaternary
structure is highly conserved from yeast to mammals. As a
serine/threonine protein phosphatase, calcineurin participates in a
number of cellular processes and Ca2+-dependent signal
transduction pathways. Calcineurin is potently inhibited by
immunosuppressant drugs, cyclosporin A and FK506, in the presence of
their respective cytoplasmic immunophilin proteins, cyclophilin and
FK506-binding protein. Many studies have used these immunosuppressant
drugs and/or modern genetic techniques to disrupt calcineurin in model
organisms such as yeast, filamentous fungi, plants, vertebrates, and
mammals to explore its biological function. Recent advances regarding
calcineurin structure include the determination of its
three-dimensional structure. In addition, biochemical and
spectroscopic studies are beginning to unravel aspects of the mechanism
of phosphate ester hydrolysis including the importance of the dinuclear
metal ion cofactor and metal ion redox chemistry, studies which may
lead to new calcineurin inhibitors. This review provides a
comprehensive examination of the biological roles of calcineurin and
reviews aspects related to its structure and catalytic mechanism.
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E. E. Spangenburg, D. K. Bowles, and F. W. Booth Insulin-Like Growth Factor-Induced Transcriptional Activity of the Skeletal {alpha}-Actin Gene Is Regulated by Signaling Mechanisms Linked to Voltage-Gated Calcium Channels during Myoblast Differentiation Endocrinology, April 1, 2004; 145(4): 2054 - 2063. [Abstract] [Full Text] [PDF]
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M. Wang, M. Tashiro, and J. R. Berlin Regulation of L-type calcium current by intracellular magnesium in rat cardiac myocytes J. Physiol., March 1, 2004; 555(2): 383 - 396. [Abstract] [Full Text] [PDF]
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P. Tavi, S. Pikkarainen, J. Ronkainen, P. Niemela, M. Ilves, M. Weckstrom, O. Vuolteenaho, J. Bruton, H. Westerblad, and H. Ruskoaho Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression J. Physiol., January 15, 2004; 554(2): 309 - 320. [Abstract] [Full Text] [PDF]
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J. H. Yoo, M. S. Cheong, C. Y. Park, B. C. Moon, M. C. Kim, Y. H. Kang, H. C. Park, M. S. Choi, J. H. Lee, W. Y. Jung, et al. Regulation of the Dual Specificity Protein Phosphatase, DsPTP1, through Interactions with Calmodulin J. Biol. Chem., January 9, 2004; 279(2): 848 - 858. [Abstract] [Full Text] [PDF]
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 T. Maeda, R. Sugiura, A. Kita, M. Saito, L. Deng, Y. He, Y. Lu, Y. Fujita, K. Takegawa, H. Shuntoh, et al. Pmr1, a P-type ATPase, and Pdt1, an Nramp homologue, cooperatively regulate cell morphogenesis in fission yeast: The importance of Mn2+ homeostasis Genes Cells, January 1, 2004; 9(1): 71 - 82. [Abstract] [Full Text] [PDF]
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Z. Hilioti, D. A. Gallagher, S. T. Low-Nam, P. Ramaswamy, P. Gajer, T. J. Kingsbury, C. J. Birchwood, A. Levchenko, and K. W. Cunningham GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs Genes & Dev., January 1, 2004; 18(1): 35 - 47. [Abstract] [Full Text] [PDF]
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C. Zambonelli, M. Casali, and M. F. Roberts Mutagenesis of Putative Catalytic and Regulatory Residues of Streptomyces chromofuscus Phospholipase D Differentially Modifies Phosphatase and Phosphodiesterase Activities J. Biol. Chem., December 26, 2003; 278(52): 52282 - 52289. [Abstract] [Full Text] [PDF]
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 M. Nagita, H. Inoue, N. Nakamura, and H. Kanazawa Two Nuclear Export Signals Specify the Cytoplasmic Localization of Calcineurin B Homologous Protein 1 J. Biochem., December 1, 2003; 134(6): 919 - 925. [Abstract] [Full Text] [PDF]
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 H. K. Manji, I. I. Gottesman, and T. D. Gould Signal Transduction and Genes-to-Behaviors Pathways in Psychiatric Diseases Sci. Signal., November 4, 2003; 2003(207): pe49 - pe49. [Abstract] [Full Text] [PDF]
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 B. Q. Xiang, Z. Jia, F. X. Xiao, K. Zhou, P. Liu, and Q. Wei The role of loop 7 in mediating calcineurin regulation Protein Eng. Des. Sel., November 1, 2003; 16(11): 795 - 798. [Abstract] [Full Text] [PDF]
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J. Ledoux, I. Greenwood, L. R Villeneuve, and N. Leblanc Modulation of Ca2+-dependent Cl- channels by calcineurin in rabbit coronary arterial myocytes J. Physiol., November 1, 2003; 552(3): 701 - 714. [Abstract] [Full Text] [PDF]
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D. Terentyev, S. Viatchenko-Karpinski, I. Gyorke, R. Terentyeva, and S. Gyorke Protein Phosphatases Decrease Sarcoplasmic Reticulum Calcium Content by Stimulating Calcium Release in Cardiac Myocytes J. Physiol., October 1, 2003; 552(1): 109 - 118. [Abstract] [Full Text] [PDF]
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R. B. Vega, R. Bassel-Duby, and E. N. Olson Control of Cardiac Growth and Function by Calcineurin Signaling J. Biol. Chem., September 26, 2003; 278(39): 36981 - 36984. [Full Text] [PDF]
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H. Kuwahara, J.-i. Kamei, N. Nakamura, M. Matsumoto, H. Inoue, and H. Kanazawa The Apoptosis-Inducing Protein Kinase DRAK2 Is Inhibited in a Calcium-Dependent Manner by the Calcium-Binding Protein CHP J. Biochem., August 1, 2003; 134(2): 245 - 250. [Abstract] [Full Text] [PDF]
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T. Miyakawa, L. M. Leiter, D. J. Gerber, R. R. Gainetdinov, T. D. Sotnikova, H. Zeng, M. G. Caron, and S. Tonegawa Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia PNAS, July 22, 2003; 100(15): 8987 - 8992. [Abstract] [Full Text] [PDF]
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S. A. Parsons, B. J. Wilkins, O. F. Bueno, and J. D. Molkentin Altered Skeletal Muscle Phenotypes in Calcineurin A{alpha} and A{beta} Gene-Targeted Mice Mol. Cell. Biol., June 15, 2003; 23(12): 4331 - 4343. [Abstract] [Full Text] [PDF]
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J. R. Blankenship, F. L. Wormley, M. K. Boyce, W. A. Schell, S. G. Filler, J. R. Perfect, and J. Heitman Calcineurin Is Essential for Candida albicans Survival in Serum and Virulence Eukaryot. Cell, June 1, 2003; 2(3): 422 - 430. [Abstract] [Full Text] [PDF]
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S.-j. Kim, W. Ding, B. Albrecht, P. L. Green, and M. D. Lairmore A Conserved Calcineurin-binding Motif in Human T Lymphotropic Virus Type 1 p12I Functions to Modulate Nuclear Factor of Activated T Cell Activation J. Biol. Chem., April 25, 2003; 278(18): 15550 - 15557. [Abstract] [Full Text] [PDF]
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 M. E. Doyle and J. M. Egan Pharmacological Agents That Directly Modulate Insulin Secretion Pharmacol. Rev., March 1, 2003; 55(1): 105 - 131. [Abstract] [Full Text] [PDF]
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J. L. Gooch, J. L. Barnes, S. Garcia, and H. E. Abboud Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation Am J Physiol Renal Physiol, January 1, 2003; 284(1): F144 - F154. [Abstract] [Full Text] [PDF]
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L. Guo, K. Nakamura, J. Lynch, M. Opas, E. N. Olson, L. B. Agellon, and M. Michalak Cardiac-specific Expression of Calcineurin Reverses Embryonic Lethality in Calreticulin-deficient Mouse J. Biol. Chem., December 20, 2002; 277(52): 50776 - 50779. [Abstract] [Full Text] [PDF]
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J. W. Neal and N. A. Clipstone Calcineurin Mediates the Calcium-dependent Inhibition of Adipocyte Differentiation in 3T3-L1 Cells J. Biol. Chem., December 13, 2002; 277(51): 49776 - 49781. [Abstract] [Full Text] [PDF]
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L F Santana, E G Chase, V S Votaw, M. T Nelson, and R Greven Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytes J. Physiol., October 1, 2002; 544(1): 57 - 69. [Abstract] [Full Text] [PDF]
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M. F. Gomez, A. S. Stevenson, A. D. Bonev, D. C. Hill-Eubanks, and M. T. Nelson Opposing Actions of Inositol 1,4,5-Trisphosphate and Ryanodine Receptors on Nuclear Factor of Activated T-cells Regulation in Smooth Muscle J. Biol. Chem., September 27, 2002; 277(40): 37756 - 37764. [Abstract] [Full Text] [PDF]
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S. J. Clarke, G. P. McStay, and A. P. Halestrap Sanglifehrin A Acts as a Potent Inhibitor of the Mitochondrial Permeability Transition and Reperfusion Injury of the Heart by Binding to Cyclophilin-D at a Different Site from Cyclosporin A J. Biol. Chem., September 13, 2002; 277(38): 34793 - 34799. [Abstract] [Full Text] [PDF]
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O. F. Bueno, E. B. Brandt, M. E. Rothenberg, and J. D. Molkentin Defective T cell development and function in calcineurin Abeta -deficient mice PNAS, July 9, 2002; 99(14): 9398 - 9403. [Abstract] [Full Text] [PDF]
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