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

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

Canine cardiac sarcoplasmic reticulum is phosphorylated by adenosine 3',5'-monophosphate (cAMP)-dependent and by calcium.calmodulin-dependent protein kinases on a 27,000 proteolipid, called phospholamban. Both types of phosphorylation are associated with an increase in the initial rates of Ca2+ transport by SR vesicles which reflects an increased turnover of elementary steps of the calcium ATPase reaction sequence. The stimulatory effects of the protein kinases on the calcium pump may be reversed by an endogenous protein phosphatase, which can dephosphorylate both the cAMP-dependent and the calcium.calmodulin-dependent sites on phospholamban. Thus, the calcium pump in cardiac sarcoplasmic reticulum appears to be under reversible regulation mediated by protein kinases and protein phosphatases.
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PMID:The role of protein kinases and protein phosphatases in the regulation of cardiac sarcoplasmic reticulum function. 284 12

Calcium fluxes across the sarcoplasmic reticulum membrane are regulated by phosphorylation of a 27,000-dalton membrane-bound protein termed phospholamban. Phospholamban is phosphorylated by three different protein kinases (cAMP-dependent, Ca2+.CAM-dependent and Ca2+.phospholipid dependent) at apparently distinct sites. Phosphorylation by each of the protein kinases increases the rates of active calcium transport by sarcoplasmic reticulum vesicles. The stimulatory effects of protein kinases on the calcium pump may be reversed by an endogenous protein phosphatase activity. The phosphoprotein phosphatase can dephosphorylate both the cAMP-dependent and the Ca2+.CAM-dependent sites of phospholamban. Phosphorylation of phospholamban also occurs in situ, in perfused beating hearts, during the peak of the inotropic response to beta-adrenergic stimulation. Reversal of the stimulatory effects is associated with dephosphorylation of phospholamban. Thus, in vivo and in vitro studies suggest that phospholamban is a regulator for the calcium pump in cardiac sarcoplasmic reticulum. The degree of phospholamban phosphorylation determined by the interaction of specific protein kinases and phosphatases may represent an important control for sarcoplasmic reticulum function and, thus, for the contraction-relaxation cycle in the myocardium. In this review, we summarize recent evidence on physical and structural properties of phospholamban, the proposed structural molecular models for this protein, and the significance of its regulatory role both in vitro and in situ.
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PMID:Regulation of cardiac sarcoplasmic reticulum function by phospholamban. 285 62

Canine cardiac sarcoplasmic reticulum is phosphorylated by an endogenous calcium-calmodulin-dependent protein kinase on a 22,000 proteolipid, called phospholamban. Phosphorylation by the calcium-calmodulin-dependent protein kinase is associated with stimulation of the initial rates of calcium transport (Davis, B. A., Schwartz, A., Samaha, F. J., and Kranias, E. G. (1983) J. Biol. Chem. 258, 13587-13591). The present study shows that protein phosphatase activity, associated with canine cardiac sarcoplasmic reticulum vesicles, can catalyze dephosphorylation of the calcium-calmodulin-dependent sites on phospholamban. The activity was maximally stimulated by manganese; fluoride was inhibitory, but its effect was reversible. Dephosphorylation of phospholamban, which was prephosphorylated by calcium-calmodulin-dependent protein kinase, resulted in a reduction of the stimulation on calcium transport rates, particularly at submaximal calcium concentrations. The decrease in calcium transport was associated with a statistically significant decrease in the apparent affinity (EC50) for calcium. Rephosphorylation of phospholamban by the endogenous calcium-calmodulin-dependent protein kinase caused full recovery of the stimulation on calcium transport rates and reversal of the effects mediated by the protein phosphatase. Thus, the calcium pump in cardiac sarcoplasmic reticulum appears to be under reversible regulation mediated by endogenous calcium-calmodulin-dependent protein kinase and protein phosphatase. Such regulation may represent an important control mechanism for the myocardium.
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PMID:Regulation of calcium transport by protein phosphatase activity associated with cardiac sarcoplasmic reticulum. 299 98

Mutants of Saccharomyces cerevisiae lacking activity of the Ca2+/calmodulin-dependent protein phosphatase calcineurin, show sensitivity to high concentrations of sodium that is partly reversed by the external supply of Ca2+. On long-time exposure to NaCl stress the mutants display an increased intracellular Na+/K+ ratio which is partially corrected by the addition of Ca2+, improving the sodium efflux of not only calcineurin-defective cells but also wild-type cells. We also demonstrate that the NaCl sensitivity of cmd mutants, expressing modified forms of calmodulin that do not bind Ca2+, is strongly reversed by the addition of Ca2+. This effect is highly dependent on calcineurin, since the NaCl tolerance of a cmd1-3 strain, carrying an additional mutation in calcineurin, is only slightly assisted by Ca2+. A striking characteristic of the loss of function of calcineurin is a several-fold increased content of intracellular Ca2+, localized mainly in subcellular compartment(s). If the compartmentalized Ca2+ pool is brought back to normal levels by an additional inactivating mutation of the vacuolar Ca2+-transporting ATPase, such double mutants do not significantly improve their tolerance to NaCl.
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PMID:A genetic analysis of the role of calcineurin and calmodulin in Ca++-dependent improvement of NaCl tolerance of Saccharomyces cerevisiae. 893 8

The sarco(endo)plasmic reticulum of animal cells contains an ATP-powered Ca2+ pump that belongs to the P-type family of membrane-bound cation-translocating enzymes. In Schistosoma mansoni, the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is encoded by the SMA1 and SMA2 genes. A full-length SMA2 cDNA clone was isolated, sequenced, and expressed into a yeast Ca2+-ATPase-deficient strain requiring plasmid-borne rabbit SERCA1a for viability. The S. mansoni Ca2+-ATPase supports growth of mutant cells lacking SERCA1a, indicating functional expression in yeast and a role in calcium sequestration. Subcellular fractionation showed that the SMA2 ATPase is localized in yeast internal membranes. SMA2 expression was found to be associated with thapsigargin-sensitive, Ca2+-dependent ATPase activity. The activity increased 2-fold upon calcineurin inactivation, which correlates with in vivo stimulated contribution of SMA2 in calcium tolerance. These results suggest that calcineurin controls calcium homeostasis by inhibiting Ca2+-ATPase activity in an internal compartment.
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PMID:Schistosoma mansoni Ca2+-ATPase SMA2 restores viability to yeast Ca2+-ATPase-deficient strains and functions in calcineurin-mediated Ca2+ tolerance. 977 93

Compared with isolated electrically driven neonatal ventricular preparations, the total time of contraction, the time to peak tension, and the time of relaxation were decreased to approximately 50% in adult ventricular preparations. The expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) was increased to 133% at the protein level and to 154% at the mRNA level in adult vs. neonatal ventricular preparations, whereas phospholamban was unchanged at both the protein and mRNA levels. Moreover, Ca2+ uptake was increased to 180% in adult vs. neonatal ventricular preparations. Phospholamban phosphorylation was enhanced in adult vs. neonatal ventricular preparations. In adult ventricular preparations, phosphatase activity was reduced to 53% of neonatal preparations, the protein levels of the immunologically detectable catalytic subunits of protein phosphatase types 1 and 2A were reduced to 28 and 61% of neonatal preparations, respectively, and the mRNA levels of type 1alpha, 1beta, 1gamma, 2Aalpha, and 2Abeta phosphatase isoforms were decreased to 69, 68, 54, 67, and 63%, respectively. We conclude that in the adult rat heart, the shortened time parameters of contraction can be explained by an elevated expression of SERCA. In addition, an increased phosphorylation state of phospholamban due to reduced phosphatase activity may be involved.
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PMID:Postnatal changes in contractile time parameters, calcium regulatory proteins, and phosphatases. 984 39

Activation of the transcription factor nuclear factor of activated T cells by the calcium-sensitive serine/threonine phosphatase calcineurin has been proposed as one of the molecular mechanisms by which motor nerve activity establishes the slow muscle phenotype. To investigate whether the calcineurin pathway can regulate the large spectrum of slow muscle characteristics in vivo, we treated rats for three weeks with cyclosporin A (an inhibitor of calcineurin). In soleus (slow muscle), but not in plantaris (fast muscle), the proportion of slow myosin heavy chain (MHC-1) and slow sarcoplasmic reticulum ATPase (SERCA2a) was decreased, whereas that of fast MHC (MHC-2A) and fast SERCA1 increased, indicating a slow to fast contractile phenotype transition. Cytosolic isoforms of creatine kinase and lactate dehydrogenase (most abundant in fast fibers), as well as mitochondrial creatine kinase and citrate synthase activities (elevated in fast/oxidative fibers) were dose dependently increased by cyclosporin A treatment in soleus muscle, with no change in plantaris. Calcineurin catalytic subunit was more abundant in soleus muscle fibers compared with plantaris. Taken together these results suggest that the calcineurin pathway co-regulates a set of multigenic protein families involved in the transition between slow oxidative (type I) to fast oxidative (type IIa) phenotype in soleus muscle.
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PMID:Calcineurin Co-regulates contractile and metabolic components of slow muscle phenotype. 1077 82

Human and experimental heart failure is characterized by increases in type-1 protein phosphatase activity, which may be partially attributed to inactivation of its endogenous regulator, protein phosphatase inhibitor-1. Inhibitor-1 represents a nodal integrator of two major second messenger pathways, adenosine 3',5'-cyclic monophosphate (cAMP) and calcium, which mediate its phosphorylation at threonine 35 and serine 67, respectively. Here, using recombinant inhibitor-1 wild-type and mutated proteins, we identified a novel phosphorylation site in inhibitor-1, threonine 75. This phosphoamino acid was phosphorylated in vitro by protein kinase Calpha independently and to the same extent as serine 67, the previous protein kinase Calpha-identified site. Generation of specific antibodies for the phosphorylated and dephosphorylated threonine 75 revealed that this site is phosphorylated in rat and dog hearts. Adenoviral-mediated expression of the constitutively phosphorylated threonine 75 inhibitor-1 in isolated myocytes was associated with specific stimulation of type-1 protein phosphatase activity and marked inhibition of the sarcoplasmic calcium pump affinity for calcium, resulting in depressed contractility. Thus, phosphorylation of inhibitor-1 at threonine 75 represents a new mechanism of cardiac contractility regulation, partially through the alteration of sarcoplasmic reticulum calcium transport activity.
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PMID:Identification of a novel phosphorylation site in protein phosphatase inhibitor-1 as a negative regulator of cardiac function. 1704 26

The basidiomycetous fungal pathogen Cryptococcus neoformans is adapted to survive challenges in the soil and environment and within the unique setting of the mammalian host. A C. neoformans mutant was isolated with enhanced virulence in a soil amoeba model that nevertheless exhibits dramatically reduced growth at mammalian body temperature (37 degrees C). This mutant phenotype results from an insertion in the ECA1 gene, which encodes a sarcoplasmic/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA)-type calcium pump. Infection in murine macrophages, amoebae (Acanthamoeba castellanii), nematodes (Caenorhabditis elegans), and wax moth (Galleria mellonella) larvae revealed that the eca1 mutants are virulent or hypervirulent at permissive growth temperatures but attenuated at 37 degrees C. Deletion mutants lacking the entire ECA1 gene were also hypersensitive to the calcineurin inhibitors cyclosporin and FK506 and to ER and osmotic stresses. An eca1Delta cna1Delta mutant lacking both Eca1 and the calcineurin catalytic subunit was more sensitive to high temperature and ER stresses than the single mutants and exhibited reduced survival in C. elegans and attenuated virulence towards wax moth larvae at temperatures that permit normal growth in vitro. Eca1 is likely involved in maintaining ER function, thus contributing to stress tolerance and virulence acting in parallel with Ca2+-calcineurin signaling.
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PMID:Eca1, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, is involved in stress tolerance and virulence in Cryptococcus neoformans. 1750 1

Thyroid hormone exerts a large number of influences on the cardiovascular system. Increased thyroid hormone action increases the force and speed of systolic contraction and the speed of diastolic relaxation and these are largely beneficial effects. Furthermore, thyroid hormone has marked electrophysiological effects increasing heart rate and the propensity for atrial fibrillation and these effects are largely mal-adaptive. In addition, thyroid hormone markedly increases cardiac angiogenesis and decreases vascular tone. These multiple thyroid hormone effects are largely mediated by the action of nuclear based thyroid hormone receptors (TR) the thyroid hormone receptor alpha and beta. TRalpha is the predominant isoform in the heart. Rapid nongenomic thyroid hormone effects also occur, which can be clearly demonstrated in ex-vivo experiments. Some of the most marked thyroid hormone effects in cardiac myocytes involve influences on calcium flux, with thyroid hormone promoting expression of the gene encoding the calcium pump of the sarcoplasmic reticulum (SERCa2). In contrast, in hypothyroid animals phospholamban levels, which inhibit the SERCa2 pump, are increased. In addition, marked effects are exerted on the calcium channel of the sarcoplasmic reticulum the ryanodine channel. Related to myofibrillar proteins, myosin heavy chain alpha is increased by T3 and MHC beta is decreased. Complex and interesting interactions occur between cardiac hypertrophy induced by excess thyroid hormone action and cardiac hypertrophy occurring with heart failure. The thyroid hormone mediated cardiac hypertrophy in its initial phases presents a physiological hypertrophy with increases in SERCa2 levels and decreased expression of MHC beta. In contrast, pressure overload induced heart failure leads to a "pathological" cardiac hypertrophy which is largely mediated by activation of the calcineurin system and the MAPkinases signaling system. Recent evidence indicates that heart failure can lead to a downregulation of the thyroid hormone signaling system in the heart. In the failing heart, decreases of thyroid hormone receptor levels occur. In addition, serum levels of T4 and T3 are decreased with heart failure in the frame of the non-thyroidal illness syndrome. The decrease in T3 serves as an indicator for a bad prognosis in the heart failure patient being linked to increased mortality. In animal models, it can be shown that in pressure overload-induced cardiac hypertrophy a decrease of thyroid hormone receptor levels occurs. Cardiac function can be improved by increasing expression of thyroid hormone receptors mediated by adeno-associated virus based gene transfer. The failing heart may develop a "hypothyroid" status contributing to diminished cardiac contractile function.
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PMID:Cardiac hypertrophy and thyroid hormone signaling. 1912 27


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