Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies with isolated membrane fractions have shown that calmodulin (CaM) inhibits the activity of cardiac muscle cell Ca(2+) release channel ryanodine receptor 2 (RyR2). To determine the physiological importance of CaM regulation of RyR2, we generated a mouse with 3 amino acid substitutions (RyR2-W3587A/L3591D/F3603A) in exon 75 of the Ryr2 gene, which encodes the CaM-binding site of RyR2. Homozygous mutant mice showed an increased ratio of heart weight to body weight, greatly reduced fractional shortening of the left ventricle, and lethality at 9-16 days of age. Biochemical analysis of hearts of 7- and 10-day-old homozygous mutant mice indicated an impaired CaM inhibition of RyR2 at micromolar Ca(2+) concentrations, reduction in RyR2 protein levels and sarcoplasmic reticulum Ca(2+) sequestration, and upregulation of genes and/or proteins associated with class II histone deacetylase/myocyte enhancer factor-2 and calcineurin signaling pathways. Sustained Ca(2+) transients, often displaying repeated periods of incomplete Ca(2+) removal, were observed in homozygous cardiomyocytes. Taken together, the data indicate that impaired CaM inhibition of RyR2, associated with defective sarcoplasmic reticulum Ca(2+) release and altered gene expression, leads to cardiac hypertrophy and early death.
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PMID:Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channel. 1743 7

We review here a novel concept in the regulation of cardiac contractility involving variations in the activity of the multifunctional enzyme, p21-activated kinase 1 (Pak1), a member of a family of proteins in the small G protein-signaling pathway that is activated by Cdc42 and Rac1. There is a large body of evidence from studies in noncardiac tissue that Pak1 activity is key in regulation of a number of cellular functions, including cytoskeletal dynamics, cell motility, growth, and proliferation. Although of significant potential impact, the role of Pak1 in regulation of the heart has been investigated in only a few laboratories. In this review, we discuss the structure of Pak1 and its sites of posttranslational modification and molecular interactions. We assemble an overview of the current data on Pak1 signaling in noncardiac tissues relative to similar signaling pathways in the heart, and we identify potential roles of Pak1 in cardiac regulation. Finally, we discuss the current state of Pak1 research in the heart in regard to regulation of contractility through functional myofilament and Ca(2+)-flux modification. An important aspect of this regulation is the modulation of kinase and phosphatase activity. We have focused on Pak1 regulation of protein phosphatase 2A (PP2A), which is abundant in cardiac muscle, thereby mediating dephosphorylation of sarcomeric proteins and sensitizing the myofilaments to Ca(2+). We present a model for Pak1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by PP2A dephosphorylation predominates.
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PMID:p21-Activated kinase-1 and its role in integrated regulation of cardiac contractility. 1760 15

Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.
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PMID:Mitochondrial and energetic cardiac phenotype in hypothyroid rat. Relevance to heart failure. 1763 11

The highly conserved RCN family of proteins regulates the serine/threonine protein phosphatase calcineurin, which is required for the expression of genes involved in Ca(2+)-dependent processes, such as the control of memory, apoptosis, T cell activation, cell cycle, Ca(2+)-homeostasis, and skeletal and cardiac muscle growth and differentiation. However, RCNs regulate calcineurin through two paradoxical actions: they act as feedback inhibitors of calcineurin, whereas their phosphorylation stimulates calcineurin. Here we show that phosphorylation of yeast RCN, Rcn1, triggers degradation through the SCF(Cdc4) ubiquitin ligase complex. Degradation of phosphorylated Rcn1 is required to mitigate inhibition of calcineurin by Rcn1 and results in activation of calcineurin activity in response to Ca(2+) as well as in reactivation of calcineurin in response to changes in Ca(2+) concentration. The SCF(Cdc4)-dependent degradation required phosphorylation of Rcn1 by Mck1, a member of the GSK3 family of protein kinases, and was promoted by Ca(2+). However, such degradation was counteracted by dephosphorylation of Rcn1, which was promoted by Ca(2+)-stimulated calcineurin. Thus, calcineurin activity is fine-tuned to Ca(2+) signals by mechanisms that have opposite functions. Our results identify the molecular mechanism of Rcn1 phosphorylation-induced stimulation of the phosphatase activity of calcineurin. The results provide insight into the mechanism involved in maintaining proper responses to Ca(2+) signals.
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PMID:The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. 1795 14

The sarco(endo)plasmic reticulum Ca(2+)-ATPase2 (SERCA2) is downregulated in cardiac hypertrophy with decompensation. We sought to determine whether mice heterozygous for the SERCA2 allele would develop greater bladder hypertrophy and decompensation than their wild-type littermates following partial bladder outlet obstruction (pBOO). We found that following 4 wk of surgically created pBOO, SERCA2 heterozygous murine bladders showed significantly less hypertrophy, improved in vitro cystometry performance, diminished expression of the slow myosin isoform A analyzed by RT-PCR, a significant drop in nuclear translocation of nuclear factor of activated T cells by EMSA, and decreased cell proliferation within the smooth muscle layer following 5-bromo-2'-deoxyuridine labeling compared with their wild-type littermates. Thus, in contrast to cardiac muscle, deletion of a SERCA2 allele confers protection against bladder hypertrophy in a murine model of pBOO. Compensatory mechanisms in heterozygous mice seem to be related to the calcineurin pathway. Further studies are underway to better define the molecular basis of this observation, which has potential clinical applications.
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PMID:Deletion of one SERCA2 allele confers protection against bladder wall hypertrophy in a murine model of partial bladder outlet obstruction. 1797 17

The Ca(2+) ATPase of sarcoplasmic reticulum has a prominent role in excitation/contraction coupling of cardiac muscle, as it induces relaxation by sequestering Ca(2+) from the cytoplasm. The stored Ca(2+) is in turn released to trigger contraction. We review here experiments demonstrating that in cardiac myocytes Ca(2+) signaling and contractile activation are strongly altered by pharmacological inhibition or transcriptional down-regulation of SERCA. On the other hand, kinetics, and intensity of Ca(2+) signaling are improved by SERCA overexpression following delivery of exogenous cDNA by adenovirus vectors. Experiments on adrenergic hypertrophy demonstrate SERCA down-regulation, consistent with its pathogenetic involvement in cardiac hypertrophy and failure, as also shown in other experimental models and clinical studies. Compensation by alternate Ca(2+) signaling proteins, including functional activation and increased expression of Na(+)/Ca(2+) exchanger and TRPC proteins has been observed. These compensatory mechanisms, including calcineurin activation, remain to be clarified and are a most important subject of current studies.
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PMID:The Ca2+ ATPase of cardiac sarcoplasmic reticulum: Physiological role and relevance to diseases. 1806 69

FoxO transcription factors contribute to cardiac muscle remodeling and insulin signaling, but how they link insulin resistance and maladaptive heart hypertrophy remains unknown. A new study by Ni et al. (2007) shows that sustained activation of FoxO1 or FoxO3 in cardiomyocytes selectively enhances the activity of Akt/PKB and reduces insulin signaling through inhibition of calcineurin and PP2A.
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PMID:Phosphatases at the heart of FoxO metabolic control. 1824 69

Hyperphosphorylation of myosin regulatory light chain (RLC) in cardiac muscle is proposed to cause compensatory hypertrophy. We therefore investigated potential mechanisms in genetically modified mice. Transgenic (TG) mice were generated to overexpress Ca2+/calmodulin-dependent myosin light chain kinase specifically in cardiomyocytes. Phosphorylation of sarcomeric cardiac RLC and cytoplasmic nonmuscle RLC increased markedly in hearts from TG mice compared with hearts from wild-type (WT) mice. Quantitative measures of RLC phosphorylation revealed no spatial gradients. No significant hypertrophy or structural abnormalities were observed up to 6 months of age in hearts of TG mice compared with WT animals. Hearts and cardiomyocytes from WT animals subjected to voluntary running exercise and isoproterenol treatment showed hypertrophic cardiac responses, but the responses for TG mice were attenuated. Additional biochemical measurements indicated that overexpression of the Ca2+/calmodulin-binding kinase did not perturb other Ca2+/calmodulin-dependent processes involving Ca2+/calmodulin-dependent protein kinase II or the protein phosphatase calcineurin. Thus, increased myosin RLC phosphorylation per se does not cause cardiac hypertrophy and probably inhibits physiological and pathophysiological hypertrophy by contributing to enhanced contractile performance and efficiency.
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PMID:Myosin regulatory light chain phosphorylation attenuates cardiac hypertrophy. 1847 88

Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect. In T-lymphocytes, FK506 binds to the intracellular receptor, a 12-kDa FK506-binding protein (FKBP12). The FK506-FKBP12 complex binds to the phosphatase calcineurin (CN) and inhibits the activity of CN. By inhibition of the activity of CN, dephosphorylation of a nuclear factor of activated T-cells (NFAT) is inhibited, and translocation of the NFAT to the nucleus is suppressed. Thereby, the production of T-cell-derived mediators such as interleukin 2 (IL-2) is inhibited, and the proliferation of cytotoxic T-cells is suppressed. In muscle cells, FKBP12 and FKBP12.6 are associated with ryanodine-sensitive Ca(2+) release channels (ryanodine receptors: RyRs) on the skeletal and cardiac muscle sarcoplasmic reticulum (SR), respectively. FK506 modulates the RyR by dissociating FKBP12 or FKBP12.6 from the RyR complex. FKBP12 is also associated with inositol 1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) release channels (IP(3) receptors: IP(3)Rs) on the endoplasmic reticulum (ER) of non-muscle cells. The IP(3)R-FKBP12 complex binds to CN, which dephosphorylates the protein kinase C (PKC) phosphorylation site on the receptor. When FKBP12 is dissociated from the IP(3)R complex by FK506, CN is also dissociated from the IP(3)R. Thereby, the IP(3)R is phosphorylated by PKC, and the receptor is modulated. Recently, it was found that FK506 itself induces Ca(2+) release through RyRs in some tissues.
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PMID:Effects of FK506 on ca release channels (review). 1978 97

Genetic defects in amino acid metabolism are major causes of newborn diseases that often lead to abnormal development and function of the central nervous system. Their direct impact on cardiac development and function has rarely been investigated. Recently, the authors have established that a mitochondrial targeted 2C-type ser/thr protein phosphatase, PP2Cm, is the endogenous phosphatase of the branched-chain alpha keto acid-dehydrogenase complex (BCKD) and functions as a key regulator in branched-chain amino acid catabolism and homeostasis. Genetic inactivation of PP2Cm in mice leads to significant elevation in plasma concentrations of branched-chain amino acids and branched-chain keto acids at levels similar to those associated with intermediate mild forms of maple syrup urine disease. In addition to neuronal tissues, PP2Cm is highly expressed in cardiac muscle, and its expression is diminished in a heart under pathologic stresses. Whereas phenotypic features of heart failure are seen in PP2Cm-deficient zebra fish embryos, cardiac function in PP2Cm-null mice is compromised at a young age and deteriorates faster by mechanical overload. These observations suggest that the catabolism of branched-chain amino acids also has physiologic significance in maintaining normal cardiac function. Defects in PP2Cm-mediated catabolism of branched-chain amino acids can be a potential novel mechanism not only for maple syrup urine disease but also for congenital heart diseases and heart failure.
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PMID:Catabolism of branched-chain amino acids in heart failure: insights from genetic models. 2121 99


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