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Physiol. Rev. 80: 1483-1521, 2000;
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Physiological Reviews, Vol. 80, No. 4, October 2000, pp. 1483-1521
Copyright ©2000 by the American Physiological Society

Calcineurin: Form and Function

Frank Rusnak and Pamela Mertz

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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Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells
J. Physiol., December 1, 2004; 561(2): 415 - 432.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
J. L. Gooch, J. J. Toro, R. L. Guler, and J. L. Barnes
Calcineurin A-{alpha} But Not A-{beta} Is Required for Normal Kidney Development and Function
Am. J. Pathol., November 1, 2004; 165(5): 1755 - 1765.
[Abstract] [Full Text] [PDF]

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 Eukaryot CellHome page
J. C. G. Cortes, R. Katoh-Fukui, K. Moto, J. C. Ribas, and J. Ishiguro
Schizosaccharomyces pombe Pmr1p Is Essential for Cell Wall Integrity and Is Required for Polarized Cell Growth and Cytokinesis
Eukaryot. Cell, October 1, 2004; 3(5): 1124 - 1135.
[Abstract] [Full Text] [PDF]

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 Mol Biol EvolHome page
T. Nagata, S. Iizumi, K. Satoh, H. Ooka, J. Kawai, P. Carninci, Y. Hayashizaki, Y. Otomo, K. Murakami, K. Matsubara, et al.
Comparative Analysis of Plant and Animal Calcium Signal Transduction Element Using Plant Full-Length cDNA Data
Mol. Biol. Evol., October 1, 2004; 21(10): 1855 - 1870.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
I. A. Greenwood, J. Ledoux, A. Sanguinetti, B. A. Perrino, and N. Leblanc
Calcineurin A{alpha} but Not A{beta} Augments ICl(Ca) in Rabbit Pulmonary Artery Smooth Muscle Cells
J. Biol. Chem., September 10, 2004; 279(37): 38830 - 38837.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
V. Dave, T. Childs, and J. A. Whitsett
Nuclear Factor of Activated T Cells Regulates Transcription of the Surfactant Protein D Gene (Sftpd) via Direct Interaction with Thyroid Transcription Factor-1 in Lung Epithelial Cells
J. Biol. Chem., August 13, 2004; 279(33): 34578 - 34588.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Coronella-Wood, J. Terrand, H. Sun, and Q. M. Chen
c-Fos Phosphorylation Induced by H2O2 Prevents Proteasomal Degradation of c-Fos in Cardiomyocytes
J. Biol. Chem., August 6, 2004; 279(32): 33567 - 33574.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. R. Swingle, R. E. Honkanen, and E. M. Ciszak
Structural Basis for the Catalytic Activity of Human Serine/Threonine Protein Phosphatase-5
J. Biol. Chem., August 6, 2004; 279(32): 33992 - 33999.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
M. D. Sans and J. A. Williams
Calcineurin is required for translational control of protein synthesis in rat pancreatic acini
Am J Physiol Cell Physiol, August 1, 2004; 287(2): C310 - C319.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J.-A. Gomez, X. Molero, E. Vaquero, A. Alonso, A. Salas, and J.-R. Malagelada
Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis
Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G162 - G169.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
J. L. Gooch, P. E. Pergola, R. L. Guler, H. E. Abboud, and J. L. Barnes
Differential Expression of Calcineurin A Isoforms in the Diabetic Kidney
J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1421 - 1429.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. H. A. Roehrl, S. Kang, J. Aramburu, G. Wagner, A. Rao, and P. G. Hogan
Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules
PNAS, May 18, 2004; 101(20): 7554 - 7559.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
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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 J. Physiol.Home page
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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 J. Physiol.Home page
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. Biol. Chem.Home page
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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 GENES CELLSHome page
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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 Genes Dev.Home page
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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 J. Biol. Chem.Home page
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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 J BiochemHome page
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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 Sci SignalHome page
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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 Protein Eng Des SelHome page
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. Physiol.Home page
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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 J. Physiol.Home page
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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 J. Biol. Chem.Home page
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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 J BiochemHome page
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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 Proc. Natl. Acad. Sci. USAHome page
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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 Mol. Cell. Biol.Home page
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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 Eukaryot CellHome page
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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 J. Biol. Chem.Home page
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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 Pharmacol. Rev.Home page
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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 Am. J. Physiol. Renal Physiol.Home page
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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