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)

Filamin is a dimeric muscle phosphoprotein that cross-links actin filaments. We have found that purified chicken gizzard filamin is phosphorylated in vitro at serine residues by the Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Up to 0.9 mol of phosphate can be incorporated into 1 mol of filamin dimer. Phosphorylation by CaM kinase II increases filamin's critical actin filament gelling concentration and diminishes the amount of actin sedimented by filamin at low G-force. The modulation of filamin function by CaM kinase II requires ATP, Ca2+, and calmodulin, and it is abolished when CaM kinase II is inactivated with heat. Protein phosphatase 2A removed the phosphate added by CaM kinase II and restored filamin's actin filament cross-linking activity to the untreated basal level. In cosedimentation experiments, phosphorylation reduces the binding of filamin to actin filaments. The Kd for binding of filamin to actin filaments increases approximately 2-fold, from 3.2 to 6.9 microM, following CaM kinase II-mediated phosphorylation. Phosphorylation by CaM kinase II, therefore, regulates the binding of filamin to actin filaments.
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PMID:Actin filament cross-linking by chicken gizzard filamin is regulated by phosphorylation in vitro. 775 5

Calponin has been implicated in the regulation of smooth muscle contraction as a result of its ability to inhibit the actin-activated Mg ATPase of smooth muscle myosin. This inhibitory effect is abolished by phosphorylation of calponin by Ca2+/calmodulin-dependent protein kinase II or protein kinase C, and restored following dephosphorylation by a type 2A protein phosphatase. Confocal immunofluorescent images of isolated smooth muscle cells colabeled with antibodies to calponin and actin or to calponin and tropomyosin indicate that calponin is present on thin filaments throughout the cell cytoplasm. Both calponin phosphorylation and myosin light chain phosphorylation increased in intact smooth muscle tissue strips when they contracted in response to carbachol or the phosphatase inhibitor okadaic acid. These results support the hypothesis that calponin phosphorylation-dephosphorylation plays a role in regulating smooth muscle contraction.
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PMID:Calponin and smooth muscle regulation. 776 87

Proliferation of mammalian cells both in vivo and in vitro is dependent upon physiological concentrations of extracellular Ca2+. Growth factor stimulation of quiescent cells at the G0/G1 border usually results in a rapid mobilization of Ca2+ from both intra- and extracellular pools. However, Ca2+ influx is also required for later phases of cell cycle transition, especially in the late G1 phase for initiation of DNA synthesis. Available evidence indicates that calmodulin plays the major and essential roles in the Ca(2+)-dependent regulation of cell proliferation. Ca2+ and calmodulin act at multiple points in the cell cycle, including the initiation of the S phase and both initiation and completion of the M phase. Ca2+ and calmodulin stimulate the expression of genes involved in the cell cycle progression, leading to activation of cyclin-dependent kinases p33cdk2 and p34cdc2. Ca2+ and calmodulin are also involved in activation of enzymes participating in nucleotide metabolism and DNA replication, as well as nuclear envelope breakdown and cytokinesis. Ca2+/calmodulin-dependent protein kinase II and protein phosphatase calcineurin are both involved in the Ca2+ and calmodulin-mediated signalling of growth regulation. As compared to normal cells, growth of transformed cells is independent of extracellular Ca2+ and much less sensitive to calmodulin antagonists, suggesting the existence of derangements in the Ca2+ and calmodulin-mediated growth regulation mechanisms.
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PMID:Calcium, calmodulin and cell cycle progression. 779 90

Protein phosphatase 2A (PP2A) isolated from whole rat brain homogenate supernatants has been compared with that extracted from rat synaptosomal membranes. Both purified enzymes are comprised of the three known PP2A polypeptide chains of 65 (A subunit), 55 (B/B' subunit), and 38 (C subunit) kDa and have okadaic acid inhibition curves (Ki = 0.05 nM) nearly identical to that reported for skeletal muscle PP2A. The isolated 38-kDa subunit of rat brain PP2A appears to contain phosphotyrosine based on cross-reactivity with a specific monoclonal antibody (PY-20). Amino acid compositions and sequences of peptides isolated from the 65- and 38-kDa species correspond to regions of the cDNA-deduced sequences of the regulatory and catalytic subunits of protein phosphatase 2A from several sources. Studies reported here also demonstrate that autophosphorylated protein kinases, particularly Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), are excellent substrates for brain PP2A. Furthermore, Ca(2+)-dependent K(+)-depolarization of hippocampal synaptosomes was accompanied by a sequential increase, then decrease, in CaM kinase II phosphorylation level over a 45-s time course. The decrease was blocked by 1 nM okadaic acid. These data demonstrate that the type 2A protein phosphatase is present at the synapses of CNS neurons where its localization could alter the functions of phosphoproteins involved in synaptic plasticity.
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PMID:Rat brain protein phosphatase 2A: an enzyme that may regulate autophosphorylated protein kinases. 779 31

The cardiac calcium release channel (CRC) of sarcoplasmic reticulum vesicles was incorporated into planar lipid membranes to evaluate modulation of channel activity by phosphorylation and dephosphorylation. For this purpose a microsyringe application directly to the membrane was used to achieve sequential and multiple treatments of channels with highly purified kinases and phosphatases. Cyclic application of protein kinase A (PKA) or Ca2+/calmodulin-dependent protein kinase II (CalPK) and potato acid phosphatase or protein phosphatase 1 revealed a channel block by Mg2+ (-mM), that is referable to dephosphorylated states of the channel, and that the Mg2+ block could be removed by phosphorylation of the CRC by either PKA or CalPK. By contrast, activation of endogenous CalPK (end CalPK) led to channel closure which could be reversed by dephosphorylation using potato acid phosphatase or protein phosphatase 1. Calmodulin by itself (which activates end CalPK in the presence of MgATP) blocks the channel in the dephosphorylated state, which can be overcome by treatment with CalPK but not PKA. Our findings reveal important insights regarding channel regulation of the ryanodine receptor: 1) the calcium release channel must be phosphorylated to be in the active state at conditions approximating physiological Mg2+ concentrations (-mM); and 2) there are multiple sites of phosphorylation on the calcium release channel with different functional consequences, which may be relevant to the regulation of E-C coupling. Phosphorylation of the CRC may be involved in recruitment of active channels, and/or it may be directly involved in each Ca2+ contraction cycle of the heart. For example, Ca2+ release may require phosphorylation of the CRC by protein kinases at sites which overcome the block by Mg2+. Inactivation may involve CRC block by calmodulin and/or phosphorylation by endogenous CalPK at the junctional face membrane.
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PMID:Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from cardiac muscle. 783 35

The modulation of the calcium release channel (CRC) by protein kinases and phosphatases was studied. For this purpose, we have developed a microsyringe applicator to achieve sequential and multiple treatments with highly purified kinases and phosphatases applied directly at the bilayer surface. Terminal cisternae vesicles of sarcoplasmic reticulum from rabbit fast twitch skeletal muscle were fused to planar lipid bilayers, and single-channel currents were measured at zero holding potential, at 0.15 microM free Ca2+, +/- 0.5 mM ATP and +/- 2.6 mM free Mg2+. Sequential dephosphorylation and rephosphorylation rendered the CRC sensitive and insensitive to block by Mg2+, respectively. Channel recovery from Mg2+ block was obtained by exogenous protein kinase A (PKA) or by Ca2+/calmodulin-dependent protein kinase II (CalPK II). Somewhat different characteristics were observed with the two kinases, suggesting two different states of phosphorylation. Channel block by Mg2+ was restored by dephosphorylation using protein phosphatase 1 (PPT1). Before application of protein kinases or phosphatases, channels were found to be "dephosphorylated" (inactive) in 60% and "phosphorylated" (active) in 40% of 51 single-channel experiments based on the criterion of sensitivity to block by Mg2+. Thus, these two states were interconvertable by treatment with exogenously added protein kinases and phosphatases. Endogenous Ca2+/calmodulin-dependent protein kinase (end CalPK) had an opposite action to exogenous CalPK II. Previously, dephosphorylated channels using PPT (Mg2+ absent) were blocked in the closed state by action of endogenous CalPK. This block was removed to normal activity by the action of either PPT or by exogenous CalPK II. Our findings are consistent with a physiological role for phosphorylation/dephosphorylation in the modulation of the calcium release channel of sarcoplasmic reticulum from skeletal muscle. A corollary of our studies is that only the phosphorylated channel is active under physiological conditions (mM Mg2+). Our studies suggest that phosphorylation can be at more than one site and, depending on the site, can have different functional consequences on the CRC.
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PMID:Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from skeletal muscle. 785 21

We investigated the role of Ca/calmodulin-dependent protein kinase (CaMKII) in relaxation and cytosolic free [Ca] ([Ca]i) decline during steady-state (SS) and postrest (PR) twitches in intact rat ventricular myocytes. Half-time of mechanical relaxation and time constant of [Ca]i decline (tau) were twofold greater during PR than with SS at 1 Hz. This difference was 1) abolished by inhibition of sarcoplasmic reticulum (SR) Ca accumulation by thapsigargin or caffeine; 2) greater at higher stimulation frequency and extracellular [Ca], which affected only SS tau; 3) abolished by the protein phosphatase inhibitor okadaic acid (10 microM, which selectively accelerated [Ca]i decline during PR); 4) still present during stimulation or inhibition of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) by 10 microM forskolin or 1 microM H-89, respectively (SS and PR tau values were abbreviated and prolonged, respectively); and 5) suppressed by 10 microM KN-62, a selective inhibitor of CaMKII, which selectively prolonged [Ca]i decline during SS twitches. Both protein kinase inhibitors were also shown to decrease the SR Ca-uptake rate in digitonin-permeabilized rat myocytes. We conclude that CaMKII plays a major role in modulation of relaxation in rat ventricular myocytes, enhancing SR Ca uptake in a activity-dependent fashion. Our results are also compatible with a background, activity-independent stimulation of SR Ca uptake by PKA in intact rat myocytes.
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PMID:CaMKII is responsible for activity-dependent acceleration of relaxation in rat ventricular myocytes. 786 97

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
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PMID:Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. 786 38

We investigated immunohistochemically the cellular localization of multifunctional type II Ca2+/calmodulin-dependent protein kinase in the rat basal ganglia and intrastriatal grafts derived from fetal striatal primordia, in comparison with that of calcineurin, a reliable marker for striatal medium-sized spinous neurons. The type II Ca2+/calmodulin-dependent protein kinase-positive neurons were of medium size, with a mean diameter of 16.1 +/- microns (average +/- S.D., n = 72, range 13.6-18.3 microns) and comprised approximately 70% of the total neuronal population in the striatum. Light microscopy showed that the type II Ca2+/calmodulin-dependent protein kinase-positive cells had round, triangular or polygonal cell bodies with relatively little cytoplasm. Analysis of serial sections showed that type II Ca2+/calmodulin-dependent protein kinase and calcineurin immunoreactivities were co-localized in the striatal neurons examined with a similar distribution pattern. Type II Ca2+/calmodulin-dependent protein kinase-positive cells were always immunoreactive for calcineurin and cells negative for type II Ca2+/calmodulin-dependent protein kinase showed no apparent calcineurin immunoreactivity. Type II Ca2+/calmodulin-dependent protein kinase-positive nerve fibers in the globus pallidus and substantia nigra almost disappeared following striatal ischemic injury produced by transient middle cerebral artery occlusion and cerebral hemitransection, respectively, suggesting that these immunopositive fibers were striatal projections. Thus, most type II Ca2+/calmodulin-dependent protein kinase-positive neurons in the rat striatum are considered to be of the medium-sized spinous type. Type II Ca2+/calmodulin-dependent protein kinase or calcineurin immunoreactivity was also observed in a large number of neurons in transplants derived from fetal striatal primordia grafted into striatal ischemic lesions. In addition, type II Ca2+/calmodulin-dependent protein kinase- or calcineurin-immunoreactive nerve fibers appeared in the deafferented globus pallidus of the host rats, suggesting that the striatopallidal pathway was reformed by striatal projection neurons of the transplants. This finding may also indicate that Ca2+/calmodulin-regulated enzymes are useful for tracing striatal projection fibers as endogenous marker proteins.
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PMID:Cellular localization of type II Ca2+/calmodulin-dependent protein kinase in the rat basal ganglia and intrastriatal grafts derived from fetal striatal primordia, in comparison with that of Ca2+/calmodulin-regulated protein phosphatase, calcineurin. 787 Mar

In the presence of costimulation, Ca2+ influx in T cells leads to activation (transcription of interleukin-2; ref. 2) via calcineurin. In the absence of costimulation, Ca2+ influx results in anergy (interleukin-2 transcriptional block) through an unknown mechanism. Specific attenuation of interleukin-2 transcriptional induction occurs in Jurkat T cells following pretreatment with a Ca2+ ionophore. A > 90% block of inducible interleukin-2 reporter gene activity was initiated by transfection of a constitutively active mutant of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase or CaM kinase II), but not by constitutive mutants of CaM kinase IV, calcineurin or protein kinase C. The block was complete six hours after kinase transfection and showed specificity for interleukin-2; there was no change in beta-actin transcription or in c-fos transcription induced by phorbol myristyl acetate, and a Rous sarcoma virus promoter was stimulated threefold. Multifunctional CaM kinase also attenuated interleukin-2 activation by calcineurin plus phorbol ester. T-cell receptor signalling activates multifunctional CaM kinase. These findings suggest that two Ca2+/calmodulin-responsive enzymes, multifunctional CaM kinase and calcineurin, could mediate the divergent effects of Ca2+ signals in T-lymphocyte regulation.
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PMID:Interleukin-2 transcriptional block by multifunctional Ca2+/calmodulin kinase. 809 Feb 6


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