Pisiferdiol restores the growth of a mutant yeast suffering from hyper-activated Ca2+-signaling through calcineurin inhibition
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Background. The major immunosuppressive effect of cyclosporine is through the inhibition of calcineurin, an enzyme important in the activation of T lymphocytes. In children, neither calcineurin activity nor its inhibition by cyclosporine (CsA) has been investigated. Methods. Calcineurin activity, was measured in stable pediatric renal transplant patients, with healthy children used as controls. Whole blood CsA concentrations were measured by monoclonal radioimmunoassay. Simultaneous calcineurin and CsA levels were measured before and 1, 2, 3.5, 5, and 12 hr after their routine morning CsA dose. Results. Calcineurin activity was approximately 50% inhibited at trough blood concentrations (148 μg/L); moreover, inhibition increased as CsA concentrations rose and declined as concentrations fell. Maximum calcineurin inhibition was about 70% at concentrations of about 431 μg/L. Linear regression analysis revealed a significant correlation between mean CsA blood concentration and the mean degree of inhibition of calcineurin activity(P=0.005, one-tailed). Conclusion. We conclude that inhibition of calcineurin activity by CsA in pediatric renal transplant recipients correlates with CsA blood concentrations.
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Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin activity was associated with an increase in calcineurin Abeta (CnAbeta) mRNA and protein, but not in CnAalpha or CnAgamma. Agonist-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. (1998) J. Biol. Chem. 273, 18325-18331]. Targeted inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting calcineurin.
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Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss‐of‐function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (Ang II ) to model the role of calcineurin in CH in adulthood. Ang II ‐induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for Ang II ‐induced CH. Surprisingly, cardiac‐specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced Ang II ‐induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that Ang II ‐induced expression of Tgfβ family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac‐specific calcineurin deletion. These results show that Ang II induces a direct, calcineurin‐dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.
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Calcium Signaling
Calcium in biology
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The protein phosphatase calcineurin mediates many cellular responses to calcium signals. Using a genetic screen in yeast, we identified a new family of proteins conserved in fungi and animals that inhibit calcineurin function when overexpressed. Overexpression of the yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibited two independent functions of calcineurin in yeast: The activation of the transcription factor Tcn1p and the inhibition of the H + /Ca 2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 bound calcineurin in vitro and inhibited its protein phosphatase activity. Signaling via calmodulin, calcineurin, and Tcn1p induced Rcn1p expression, suggesting that Rcn1p operates as an endogenous feedback inhibitor of calcineurin. Surprisingly, rcn1 null mutants exhibited phenotypes similar to those of Rcn1p-overexpressing cells. This effect may be due to lower expression of calcineurin in rcn1 mutants during signaling conditions. Thus, Rcn1p levels may fine-tune calcineurin signaling in yeast. The structural and functional conservation between Rcn1p and DSCR1 suggests that the mammalian Rcn1p-related proteins, termed calcipressins, will modulate calcineurin signaling in humans and potentially contribute to disorders such as Down Syndrome.
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To the Editor: The calcineurin pathway has been proposed to mediate left ventricular hypertrophy, particularly its initiation. 1 However, evidence has been scant. Braun et al 2 designed a very interesting experimental protocol and investigated whether calcineurin expression was up-regulated at the initial stage of left ventricular hypertrophy. Unfortunately, they failed to detect calcineurin overexpression. There are a couple of problems with the methodology they employed in the study. First, it appears that they homogenized the whole heart instead of the left ventricle only, which may dilute calcineurin expression. Second, calcineurin upregulation represents both increased calcineurin expression and increased calcineurin activity. Apparently, the activity was not measured in the study, as the assay for calcineurin has not been perfected. 3,4 As such, it remains unclear whether calcineurin plays an important role at an early stage in isoproterenol-induced cardiac hypertrophy. 5 Isuzu Yamori, MD
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Journal Article FKBP12-FK506 Complex Inhibits Phosphatase Activity of Two Mammalian Isoforms of Calcineurin Irrespective of Their Substrates or Activation Mechanisms1 Get access Hideyuki Mukai, Hideyuki Mukai *Department of Pharmacology, Kobe University School of MedicineChuo-ku, Kobe 650 Search for other works by this author on: Oxford Academic PubMed Google Scholar Takayoshi Kuno, Takayoshi Kuno 2 *Department of Pharmacology, Kobe University School of MedicineChuo-ku, Kobe 650 2To whom correspondence should be addressed. Search for other works by this author on: Oxford Academic PubMed Google Scholar Chang-Duk Chang, Chang-Duk Chang *Department of Pharmacology, Kobe University School of MedicineChuo-ku, Kobe 650 Search for other works by this author on: Oxford Academic PubMed Google Scholar Ben Lane, Ben Lane **Immunoscience Research, Pharmaceutical Products Division, Abbott LaboratoriesAbbott Park, IL 60064-3500, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Jay R. Luly, Jay R. Luly **Immunoscience Research, Pharmaceutical Products Division, Abbott LaboratoriesAbbott Park, IL 60064-3500, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Chikako Tanaka Chikako Tanaka *Department of Pharmacology, Kobe University School of MedicineChuo-ku, Kobe 650 Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Biochemistry, Volume 113, Issue 3, March 1993, Pages 292–298, https://doi.org/10.1093/oxfordjournals.jbchem.a124041 Published: 01 March 1993 Article history Received: 29 October 1992 Published: 01 March 1993
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The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation.
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