Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac hypertrophy occurs in a number of disease states associated with chronic increases in cardiac work load. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure. Much investigation has focused on the signaling pathways controlling cardiac hypertrophy at the level of the single cardiac myocyte. One prohypertrophic pathway that has received much attention involves the ubiquitously expressed Ca2+/calmodulin-activated phosphatase calcineurin. Upon activation by Ca2+, calcineurin dephosphorylates nuclear factor of activated T cell (NFAT) transcription factors, leading to their nuclear translocation. As common in complex biological systems, cardiac hypertrophy is controlled simultaneously by stimulatory (prohypertrophic) and counter-regulatory (antihypertrophic) pathways. Given the potent prohypertrophic effects of the Ca2+-calcineurin-NFAT pathway in cardiac myocytes, it is not surprising that the activity of this pathway is tightly controlled at multiple levels. Inhibitory mechanisms upstream (nitric oxide (NO), cGMP, cGMP-dependent protein kinase type I (PKG I), heme oxygenase-1 (HO-1), biliverdin, carbon monoxide (CO)) and downstream from calcineurin (glycogen synthase kinase-3 (GSK3), c-Jun N-terminal kinases (JNKs), p38 mitogen-activated protein kinase (MAPKs)) have been described. Moreover, several inhibitors directly target calcineurin enzymatic activity (cyclosporine A (CsA), tacrolimus (FK506), calcineurin-binding protein-1 (Cabin-1)/calcineurin-inhibitory protein (Cain), A-kinase-anchoring protein-79 (AKAP79), calcineurin B homology protein (CHP), MCIPs, VIVIT). Considering the dominant role of the calcineurin pathway in cardiac hypertrophy and failure, calcineurin-inhibitory strategies may lead to the identification of novel therapeutic approaches for patients with cardiac disease.
...
PMID:Interference of antihypertrophic molecules and signaling pathways with the Ca2+-calcineurin-NFAT cascade in cardiac myocytes. 1527 70

Myocardial hypertrophy is an independent risk factor for development of heart failure. The intracellular calcium homeostasis is altered in myocardial hypertrophy, and recent studies in animal models have confirmed an interaction between the Ca2+/calmodulin-dependent calcineurin signaling cascade and development of cardiac hypertrophy. There is evidence for the involvement of various pathways in development of hypertrophy. A transgenic rat model overexpressing the mouse renin gene, TGR(mREN2)27 has been shown to progress profound cardiac hypertrophy, possibly due to a monogenetic disorder. However, the exact mode of action is not known. To study a possible involvement of calcineurin and its downstream pathway in development of cardiac hypertrophy in this transgenic rat model we measured the protein expression of marker proteins of the calcineurin cascade (calcineurin, NFAT-3, GATA-4) and calcineurin phosphatase activity and GATA-4 DNA binding in TGR ( n=10) compared to age-matched Sprague-Dawley rats ( n=10). In our study there was no significant difference in calcineurin activity between the transgenic hearts and the hearts of Sprague-Dawley rats. Furthermore, we found neither an increase in protein expression of calcineurin B nor a rise in nuclear translocated NFAT-3 DU. Interestingly, the protein expression of GATA-4 and its DNA binding activity were significantly higher in hypertrophied myocardium than in control hearts. In transgenic rats overexpressing the mouse renin gene and thereby developing pronounced cardiac hypertrophy [TGR(mREN2)27] we thus found no activation of calcineurin or its downstream pathway. However, the expression of the transcriptional factor GATA-4 and its DNA binding activity were significantly increased in hearts of transgenic rats. Thus GATA-4 seems to be a marker of hypertrophy independently of calcineurin activation, possibly activated by various pathways.
...
PMID:Calcineurin independent development of myocardial hypertrophy in transgenic rats overexpressing the mouse renin gene, TGR(mREN2)27. 1537 67

Calcineurin is a calcium/calmodulin-dependent serine/ threonine protein phosphatase. It is a heterodimeric protein consisting of a catalytic subunit calcineurin A, and a regulatory calcium-binding subunit, calcineurin B. The primary sequence of both subunits and heterodimeric structure is highly conserved from yeast to mammals. Calcineurin has long been implicated in various signaling pathways. Calcineurin genes (cna-1/tax-6 and cnb-1) have been identified in the nematode Caenorhabditis elegans, which share high homology with their Drosophila and mammalian counterparts. C. elegans calcineurin binds calcium and functions as a heterodimeric protein phosphatase establishing its biochemical conservation. Calcineurin expresses in diverse tissues implicating its important role in various physiological processes. This review will focus in brief on the expression pattern and regulation of calcineurin including its effect on growth and development, locomotion, egg-laying, and sensory responses.
...
PMID:Regulation of calcineurin, a calcium/calmodulin-dependent protein phosphatase, in C. elegans. 1535 18

Calcineurin (CN), a Ca(2+)/calmodulin (CaM)-dependent serine/threonine protein phosphatase, is a heterodimer composed of a catalytic subunit (CNA) and a regulatory subunit (CNB). The activity of CNA is under the control of two functionally distinct, but structurally similar Ca(2+)-regulated proteins, CaM and CNB. The crystal structure of the holoenzyme reveals that the N-terminus and C-terminus of CNB and the N-terminus of CNA each have a long arm not involved in the active site. We constructed a fusion of the genes of CaM, CNB and CNA in that order using linker primers containing six and ten codons of glycine. A single-chain CaM-CNB-CNA (CBA) complex was expressed and purified to near homogeneity. The single-chain complex was fully soluble, and had biochemical properties and kinetic parameters similar to single-chain CNB-CNA (BA) activated by CaM. It was not regulated by CaM and CNB, but was strongly stimulated by Mn2+, Ni2+ and Mg2+. Intrinsic fluorescence spectroscopy of the complex showed a change in the environment of tryptophan in the presence of Ca2+ and circular dichroism (CD) spectropolarimetry revealed an increase in alpha-helical content. Our findings suggest that fusion of CaM, CNB and CNA does not prevent the structural changes required for their functioning; in particular, CaM within the complex could still interact correctly with CN in the presence of Ca2+.
...
PMID:Preparation and characterization of a single-chain calcineurin-calmodulin complex. 1569 51

Calcium- and integrin-binding protein 1 (CIB1) is involved in the process of platelet aggregation by binding the cytoplasmic tail of the alpha(IIb) subunit of the platelet-specific integrin alpha(Iib)beta(3). Although poorly understood, it is widely believed that CIB1 acts as a global signaling regulator because it is expressed in many tissues that do not express integrin alpha(Iib)beta(3). We report the structure of human CIB1 to a resolution of 2.3 A, crystallized as a dimer. The dimer interface includes an extensive hydrophobic patch in a crystal form with 80% solvent content. Although the dimer form of CIB1 may not be physiologically relevant, this intersub-unit surface is likely to be linked to alpha(IIb) binding and to the binding of other signaling partner proteins. The C-terminal domain of CIB1 is structurally similar to other EF-hand proteins such as calmodulin and calcineurin B. Despite structural homology to the C-terminal domain, the N-terminal domain of CIB1 lacks calcium-binding sites. The structure of CIB1 revealed a complex with a molecule of glutathione in the reduced state bond to the N-terminal domain of one of the two subunits poised to interact with the free thiol of C35. Glutathione bound in this fashion suggests CIB1 may be redox regulated. Next to the bound GSH, the orientation of residues C35, H31, and S48 is suggestive of a cysteine-type protein phosphatase active site. The potential enzymatic activity of CIB1 is discussed and suggests a mechanism by which it regulates a wide variety of proteins in cells in addition to platelets.
...
PMID:The crystal structure of calcium- and integrin-binding protein 1: insights into redox regulated functions. 1584 Aug 29

Protein phosphatase 3 (PPP3, formerly PP2B, Calcineurin), a serine/threonine protein phosphatase, is a heterodimer composed of one catalytic subunit (PPP3C, Calcineurin A) and one regulatory subunit (PPP3R, Calcineurin B). PPP3R, an EF-hand Ca2+ binding protein, contains four high-affinity EF-hand calcium-binding sites, indicating that PPP3 plays critical roles in many calcium-mediated signal transduction pathways. PPP3R has two isoforms, PPP3R1 (also known as PP2Bbeta1) and PPP3R2 (also known as PP2BB2). While PPP3R1 is ubiquitously expressed in different tissues, PPP3R2 is exclusively expressed in testis. PPP3R2 has only been identified in rat and mouse. Here we report a human homologue of PPP3R2, which is designated PPP3RL (PPP3R like protein). PPP3RL gene was predicated to encode 171 amino acid residues with four EF-hand calcium-binding domains and this putative protein shares 82.9% and 80.5% identity with PPP3R2 of rat and mouse, respectively. Our results show that PPP3RL gene localizes to human chromosome 9q22 and transcripts of PPP3RL gene are specifically expressed in the testis, moreover, this tissue-specific expression is due to demethylation of its promoter region in testis.
...
PMID:Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis. 1586 9

The enteric muscle contraction (EMC) is the last step of the defecation behavior which occurs every 50 s in Caenorhabditis elegans. This EMC is regulated by intestinal and anal depressor muscles, which are innervated by GABA motor neurons. Our data show that calcineurin (tax-6) is expressed in intestinal muscle and anal depressor muscle, and the gain-of-function mutant of calcineurin, tax-6(jh107), shows defects in enteric muscle contractions. In addition, the intracellular region of EXP-1, an excitatory GABA receptor, specifically binds to calcineurin A. This interaction between TAX-6 and EXP-1 appears to be independent of both calcium and CNB, which is the calcium-binding regulatory subunit. Genetic evidence of epistasis between cnb-1(jh103) and exp-1(sa6) suggests that calcineurin functions as a negative regulator of excitatory GABA receptor in GABA signaling in C.elegans.
...
PMID:Calcineurin regulates enteric muscle contraction through EXP-1, excitatory GABA-gated channel, in C. elegans. 1608 27

The calcium-calmodulin-activated protein phosphatase calcineurin functions as a key mediator of diverse biologic processes, including differentiation, apoptosis, growth, and adaptive responses, in part through dephosphorylation and activation of nuclear factor of activated T-cell (NFAT) transcription factors. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream component of the mitogen-activated protein kinases that serves as a pivotal regulator of cytokine-, oxidative-, and stress-induced cell death. Here, we performed a yeast two-hybrid screen with calcineurin B as bait, which identified ASK1 as a direct physical interacting partner. The C-terminal 218 amino acids of ASK1 were sufficient to mediate interaction with calcineurin B in yeast, as well as in mammalian cell lysates. Importantly, endogenous calcium binding B subunit (CnB) protein interacted with endogenous ASK1 protein in cardiomyocytes at baseline, suggesting that the interaction observed in yeast was of potential biologic relevance. Indeed, calcineurin directly dephosphorylated ASK1 at serine 967 using purified proteins or mammalian cell lysates. Dephosphorylation of ASK1 serine 967 by calcineurin promoted its disassociation from 14-3-3 proteins, resulting in ASK1 activation. Calcineurin and ASK1 cooperatively enhanced cardiomyocyte apoptosis, while expression of a dominant negative ASK1 blocked calcineurin-induced apoptosis. Mouse embryonic fibroblasts deficient in ask1 were also partially resistant to calcineurin- or ionomycin-induced apoptosis. Finally, ASK1 negatively regulated calcineurin-NFAT signaling indirectly through c-Jun NH2-terminal kinase (JNK)- and p38-mediated phosphorylation of NFAT, which blocked calcineurin- and agonist-dependent hypertrophic growth of cardiomyocytes. Thus, ASK1 and calcineurin-NFAT constitute a feedback regulatory circuit in which calcineurin positively regulates ASK1 through direct dephosphorylation, while ASK1 negatively regulates calcineurin-NFAT signaling through p38- and JNK-mediated NFAT phosphorylation.
...
PMID:Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth. 1664 74

Large conductance calcium-activated potassium (BK(Ca)) channels are regulated by a number of different protein kinases and phosphatases. The close association of enzymes and channel have been shown to underlie many examples of modulation. However, only the association of protein kinase A with the BK(Ca) channel has been detailed [Tian et al. (2003)J. Biol. Chem., 278, 8669-8677]. We have found using reciprocal immunoprecipitations that the BK(Ca) channel associates with the calcium/calmodulin-dependent phosphatase calcineurin, in Wistar rat brain. A HA-tagged construct of the carboxyl terminus of rSlo(27), a variant of the BK(Ca) channel that is abundant in the hippocampus [Ha et al. (2000)Eur. J. Biochem., 267, 910-9218], was found to associate only with the B subunit of calcineurin. This data suggests that the majority of the interaction of the BK(Ca) channel with calcineurin is mediated by the B subunit of the phosphatase. This was confirmed by using glutathione-S-transferase (GST) fusion proteins of the linker regions between the S7-S10 hydrophobic domains in the carboxyl terminus of rSlo(27), where only the B subunit of calcineurin interacted with regions between S7 and S9 of the channel. Addition of a constitutively active calcineurin (CaN(420)) to inside-out membrane patches excised from cultured hippocampal neurons resulted in a dramatic reduction in BK(Ca) channel open probability, with only very short-duration events being apparent. These data suggest that BK(Ca) channel activity is inhibited by calcineurin, an effect mediated by the association of the calcineurin B subunit with the carboxyl terminus of the channel.
...
PMID:Inhibition of BK channel activity by association with calcineurin in rat brain. 1690 51

During early postnatal development, the myosin heavy chain (MyHC) expression pattern in equine gluteus medius muscle shows adaptation to movement and load,resulting in a decrease in the number of fast MyHC fibers and an increase in the number of slow MyHC fibers. In the present study we correlated the expression of MyHC isoforms to the expression of sarcoplasmic(endo)reticulum Ca2+-ATPase 1 and 2a (SERCA), phospholamban (PLB), calcineurin A (CnA), and calcineurin B (CnB). Gluteus medius muscle biopsies were taken at 0, 2, 4, and 48 weeks and analyzed using immunofluorescence. Both SERCA isoforms and PLB were expressed in almost all fiber types at birth. From 4 weeks of age onward, SERCA1 was exclusively expressed in fast MyHC fibers and SERCA2a and PLB in slow MyHC fibers. At all time points, CnA and CnB proteins were expressed at a basal level in all fibers, but with a higher expression level in MyHC type 1 fibers. From 4 weeks onward, expression of only CnA was also higher in MyHC type 2a and 2ad fibers. We propose a double function of calcineurin in calcium homeostasis and maintenance of slow MyHC fiber type identity. Although equine muscle is already functional at birth, expression patterns of the monitored proteins still show adaptation, depending on the MyHC fiber type.
...
PMID:Differential expression of calcineurin and SR Ca2+ handling proteins in equine muscle fibers during early postnatal growth. 1710 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---