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:2.7.11.17 (CaMKII)
4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to characterize the second messenger activated protein kinase and phosphatase systems in chick ciliary ganglion using biochemical and immunochemical techniques. Using synthetic peptide substrates cyclic-AMP-, cyclic-GMP-, Ca2+/calmodulin- and Ca2+/phospholipid-dependent protein kinase activities were detected in homogenates of ciliary ganglion dissected from 15-16-day-old embryos. Autophosphorylation of the alpha and beta subunits of Ca2+/calmodulin-dependent protein kinase II in the presence of Ca2+/calmodulin or 5 mM ZnSO4 was detected by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and autoradiography. Protein kinase C was shown to be present using a monoclonal antibody. Two cyclic-AMP binding proteins whose molecular weights corresponded to the regulatory subunits of cyclic AMP-dependent protein kinase (RI and RII) were detected in ciliary ganglia using 8-azido-cyclic-AMP. The most heavily labelled band following incubation with [gamma-32P]ATP under most conditions had an apparent molecular weight of 65,000 which corresponds to the chicken form of myristoylated alanine-rich C kinase substrate, a known substrate of protein kinase C. Another substrate for protein kinase C was a 45,000 molecular weight protein which was tentatively identified as neuromodulin (B-50/GAP-43). Although no endogenous substrate proteins for cyclic-GMP-dependent protein kinase were detected, protein kinase A strongly labelled a 40,000 molecular weight protein. Using 32P(i)-labelled glycogen phosphorylase, protein phosphatases 1 and 2A were identified in ciliary ganglia homogenates at levels which were indistinguishable from forebrain at the same age. The major endogenous protein substrates in ciliary ganglion homogenates from 15-16-day-old embryos were also labelled to a similar extent in homogenates of ciliary ganglia from newly hatched chickens. Intact ciliary ganglia remained viable for several hours after dissection and, after incubation with 32P(i), responded to phorbol ester stimulation by an increased endogenous phosphorylation of several proteins, but especially myristoylated alanine-rich C kinase substrate. These results represent the first systematic characterization of the protein phosphorylation systems in chicken ciliary ganglion and provide a basis for future studies on the biochemical mechanisms responsible for regulating synaptic transmission in this tissue.
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PMID:Characterization of protein kinase and phosphatase systems in chick ciliary ganglion. 884 61

Type I adenylyl cyclase is a neurospecific enzyme that is stimulated by Ca2+ and calmodulin (CaM). This enzyme couples the Ca2+ and cyclic AMP (cAMP) regulatory systems in neurons, and it may play an important role for some forms of synaptic plasticity. Mutant mice lacking type I adenylyl cyclase show deficiencies in spatial memory and altered long-term potentiation (Z. Wu, S. A. Thomas, Z. Xia, E. C. Villacres, R. D. Palmiter, and D. R. Storm, Proc. Natl. Acad. Sci. USA 92:220-224, 1995). Although type I adenylyl cyclase is synergistically stimulated by Ca2+ and G-protein-coupled receptors in vivo, very little is known about mechanisms for inhibition of the enzyme. Here, we report that type I adenylyl cyclase is inhibited by CaM kinase IV in vivo. Expression of constitutively active or wild-type CaM kinase IV inhibited Ca2+ stimulation of adenylyl cyclase activity without affecting basal or forskolin-stimulated activity. Type I adenylyl cyclase has two CaM kinase IV consensus phosphorylation sequences near its CaM binding domain at Ser-545 and Ser-552. Conversion of either serine to alanine by mutagenesis abolished CaM kinase IV inhibition of adenylyl cyclase. This suggests that the activity of this enzyme may be directly inhibited by CaM kinase IV phosphorylation. Type VIII adenylyl cyclase, another enzyme stimulated by CaM, was not inhibited by CaM kinase II or IV. We propose that CaM kinase IV may function as a negative feedback regulator of type I adenylyl cyclase and that CaM kinases may regulate cAMP levels in some cells.
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PMID:Regulation of type I adenylyl cyclase by calmodulin kinase IV in vivo. 888 37

While changes in gene expression are critical for many brain functions, including long-term memory, little is known about the cellular processes that mediate stimulus-transcription coupling at central synapses. In studying the signaling pathways by which synaptic inputs control the phosphorylation state of cyclic AMP-responsive element binding protein (CREB) and determine expression of CRE-regulated genes, we found two important Ca2+/calmodulin (CaM)-regulated mechanisms in hippocampal neurons: a CaM kinase cascade involving nuclear CaMKIV and a calcineurin-dependent regulation of nuclear protein phosphatase 1 activity. Prolongation of the synaptic input on the time scale of minutes, in part by an activity-induced inactivation of calcineurin, greatly extends the period over which phospho-CREB levels are elevated, thus affecting induction of downstream genes.
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PMID:CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. 898 Feb 27

We investigated the expression of regulatory (R) and catalytic (C) subunits of cyclic AMP-dependent protein kinase (cAK; ATP:protein phosphotransferase; EC 2.7.1.37) in the bovine pineal gland. In total RNA extracts of bovine pineal glands moderate levels of RI alpha/RII beta and high levels of C alpha and C beta mRNA were found. We were able to detect a strong signal for RII and C subunit at the protein level, whereas RI was apparently absent. Probing sections of the intact bovine pineal gland with RI and RII antibodies stained only RII in pinealocytes. Pairs of cyclic AMP analogues complementing each other in activation of type II cAK, but not cAKI-directed analogue pairs, showed synergistic stimulation of melatonin synthesis. Moreover, melatonin synthesis stimulated by the physiological activator norepinephrine in pineal cell cultures was inhibited by cAK antagonists. Taken together these results show the presence of RII regulatory and both C alpha and C beta catalytic subunits and thus cAKII holoenzyme in the bovine pineal gland. The almost complete inhibition of norepinephrine-mediated melatonin synthesis by the cAK antagonists emphasizes the dominant role of cyclic AMP as the second messenger and cAK as the transducer in bovine pineal signal transduction.
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PMID:Melatonin synthesis in the bovine pineal gland is regulated by type II cyclic AMP-dependent protein kinase. 900 68

Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is a monomeric multifunctional enzyme that is expressed only in subanatomical portions of the brain, T lymphocytes, and postmeiotic male germ cells. It is present in the nucleus of the cells in which it is expressed and can phosphorylate and activate the cyclic AMP response element binding proteins CREB and CREM tau in a manner analogous to protein kinase A. In the absence of Ca2+/calmodulin, CaMKIV is inactive. Activation requires three events: 1) binding of Ca2+/calmodulin; 2) phosphorylation of a single threonine residue present in the activation loop by a separate protein kinase that is also Ca2+/calmodulin-dependent; and 3) autophosphorylation of serine residues present in the extreme N-terminus that is required to relieve a novel form of autoinhibition. The gene for rat CaMKIV has been cloned and found to span 42 kb of DNA. The gene encodes three proteins: namely, the alpha and beta forms of CaMKIV that differ only in that the beta form contains a 28 amino acid N-terminal extension as well as calspermin. Calspermin is the C-terminal 169 amino acids of CaMKIV that binds Ca2+/calmodulin and is expressed only in postmeiotic male germ cells. The promoter for calspermin resides in the penultimate intron of the CaMKIV gene and is regulated by two CREs. This promoter is sufficient to faithfully target expression of a reporter gene to the postmeiotic male germ cells of transgenic mice. Transgene expression can be induced in cells from the transgenic mice that do not normally express it by transfection of CREM tau and CaMKIV. These data suggest that rearrangement of chromatin during meiosis together with the expression of CREM tau at high levels are sufficient to control expression of the calspermin promoter during spermatogenesis. On the other hand, the developmental expression of CaMKIV in brain and thymus appears to be controlled by thyroid hormone mediated via the thyroid hormone receptor alpha. In T lymphocytes, CaMKIV will phosphorylate CREB in response to signals that result in T cell activation. Transgenic mice that express a kinase minus mutant of CaMKIV specifically in thymic T cells show a marked reduction of total thymic cellularity. The remaining T cells undergo a much greater than normal rate of spontaneous apoptosis when placed in culture. These cells fail to generate the signals to phosphorylate CREB and produce significantly less of the cytokine Interleukin-2 (IL-2) in response to agents that either increase intracellular Ca2+ and/or activate protein kinase C. Collectively, the data suggest that CaMKIV may be involved both in preventing apoptosis during T cell development and also in the early cascade of events that is required to activate the mature T cells in response to a mitogenic stimulus.
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PMID:Regulation and properties of the rat Ca2+/calmodulin-dependent protein kinase IV gene and its protein products. 923 60

Electric tissue of the electric eel, Electrophorus electricus, has been used extensively as a model system for the study of excitable membrane biochemistry and electrophysiology. Membrane receptors, ion channels, and ATPases utilized by electrocytes are conserved in mammalian neurons and myocytes. In this study, we show that Ca2+ predominates as the major mediator of electric tissue phosphorylation relative to cyclic AMP and cyclic GMP-induced phosphorylation. Mastoparan, a calmodulin inhibitor peptide, and a peptide corresponding to the pseudosubstrate region of mammalian calmodulin-dependent protein kinase II (CaMKII (281-302)) attenuated Ca(2+)-dependent phosphorylation in a dose-dependent manner. These experiments demonstrated that calmodulin-dependent protein kinase II activity predominates in electric tissue. The Electrophorus kinase was purified by a novel affinity chromatography procedure utilizing Ca2+/calmodulin-dependent binding to the CaMKII (281-302) peptide coupled to Sepharose. The purified 51 kDa calmodulin-dependent protein kinase II demonstrated extensive autophosphorylation and exhibited a 3- to 4-fold increase in Ca(2+)-independent activity following autophosphorylation. Immunofluorescent localization experiments demonstrated calmodulin to be abundant in electrocytes, particularly subjacent to the plasma membrane. Calmodulin-dependent protein kinase II had a punctate distribution indicating that it may be compartmentalized by association with vesicles or the cytoskeleton. As the primary mediator of phosphorylation within electric tissue, CaM kinase II may be critical for the regulation of the specialized electrophysiological function of electrocytes.
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PMID:A major second messenger mediator of Electrophorus electricus electric tissue is CaM kinase II. 924 14

To determine the mechanisms responsible for the termination of Ca2+-activated Cl- currents (ICl(Ca)), simultaneous measurements of whole cell currents and intracellular Ca2+ concentration ([Ca2+]i) were made in equine tracheal myocytes. In nondialyzed cells, or cells dialyzed with 1 mM ATP, ICl(Ca) decayed before the [Ca2+]i decline, whereas the calcium-activated potassium current decayed at the same rate as [Ca2+]i. Substitution of AMP-PNP or ADP for ATP markedly prolonged the decay of ICl(Ca), resulting in a rate of current decay similar to that of the fall in [Ca2+]i. In the presence of ATP, dialysis of the calmodulin antagonist W7, the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN93, or a CaMKII-specific peptide inhibitor the rate of ICl(Ca) decay was slowed and matched the [Ca2+]i decline, whereas H7, a nonspecific kinase inhibitor with low affinity for CaMKII, was without effect. When a sustained increase in [Ca2+]i was produced in ATP dialyzed cells, the current decayed completely, whereas in cells loaded with 5'-adenylylimidodiphosphate (AMP-PNP), KN93, or the CaMKII inhibitory peptide, ICl(Ca) did not decay. Slowly decaying currents were repeatedly evoked in ADP- or AMP-PNP-loaded cells, but dialysis of adenosine 5'-O-(3-thiotriphosphate) or okadaic acid resulted in a smaller initial ICl(Ca), and little or no current (despite a normal [Ca2+]i transient) with a second stimulation. These data indicate that CaMKII phosphorylation results in the inactivation of calcium-activated chloride channels, and that transition from the inactivated state to the closed state requires protein dephosphorylation.
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PMID:Inactivation of calcium-activated chloride channels in smooth muscle by calcium/calmodulin-dependent protein kinase. 940 14

In previous work we showed that phosphorylation of the astrocyte marker glial fibrillary acidic protein (GFAP) in hippocampal slices from adult rats is dependent on external Ca2+, whereas in slices from immature rats aged 12-16 days postnatal 32P incorporation into GFAP is inhibited by external Ca2+. The nature of this late developmental change in Ca2+ sensitivity for GFAP phosphorylation was investigated in the present work by comparing in immature and adult animals phosphorylation of GFAP by endogenous protein kinase activity in cytoskeletal fractions and tryptic phosphopeptide maps prepared from cytoskeletal fractions labelled with [gamma-32P]ATP and from slices labelled with [32P]phosphate. Cytoskeletal fractions prepared from immature and adult hippocampus both contained endogenous protein kinase activity towards GFAP and other proteins stimulated by Ca2+/calmodulin and by cyclic AMP. The maps of GFAP isolated from the cytoskeletal fractions labelled in the presence of Ca2+/calmodulin were very similar and exhibited two major and several minor phosphopeptides. Comparison with maps derived from these fractions labelled in the presence of cyclic AMP showed that one of the major phosphopeptides was either directly or indirectly phosphorylated by Ca2+/calmodulin-stimulated kinase activity. Maps derived from GFAP isolated from adult slices labelled in the presence of Ca2+ and immature slices labelled in the absence of Ca2+ were qualitatively identical, with minor differences from the cytoskeletal maps. At both ages the slice maps displayed the phosphopeptide phosphorylated through the activity of a Ca2+/calmodulin kinase in the cytoskeletal fractions. By its migration properties this peptide appears to correspond to a sequence containing a site shown by other workers to be phosphorylated in vitro by CaM kinase II, suggesting that even in the absence of external Ca2+, kinase activity directly or indirectly dependent on Ca2+ was occurring in the immature slices. The near identity of the phosphorylation sites at the two ages suggest that the change in Ca2+ sensitivity of GFAP phosphorylation during development is not due to a change in the balance of kinase and phosphatase activities, but rather to a change in the mechanism(s) whereby Ca2+ controls the relative activity of these enzymes.
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PMID:Calcium-dependent phosphorylation of glial fibrillary acidic protein (GFAP) in the rat hippocampus: a comparison of the kinase/phosphatase balance in immature and mature slices using tryptic phosphopeptide mapping. 946 2

The Ca2+/calmodulin-dependent protein phosphatase 2B or calcineurin (CN) participates in several Ca2+-dependent signal transduction cascades and, thus, contributes to the short and long term regulation of neuronal excitability. By using a specific antibody to CN, we demonstrate its absence from hippocampal interneurons and illustrate a physiological consequence of such CN deficiency. Consistent with the lack of CN in interneurons as detected by immunocytochemistry, the CN inhibitors FK-506 or okadaic acid significantly prolonged N-methyl-D-aspartate channel openings recorded in the cell-attached mode in hippocampal principal cells but not those recorded in interneurons. Interneurons were also devoid of Ca2+/calmodulin-dependent protein kinase IIalpha, yet many of their nuclei contained the cyclic AMP-responsive element binding protein. On the basis of the CN and Ca2+/calmodulin-dependent protein kinase IIalpha deficiency of interneurons, entirely different biochemical mechanisms are expected to govern Ca2+-dependent neuronal plasticity in interneurons versus principal cells.
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PMID:The absence of a major Ca2+ signaling pathway in GABAergic neurons of the hippocampus. 950 Dec 48

In canine cerebral artery strips contracted with prostaglandin F2alpha, transmural electrical stimulation (5 Hz for 40 s) produced a relaxation which was abolished by tetrodotoxin. The neurogenic response was inhibited moderately by [S]-5-isoquinolinesulfonic acid,4-[2-[(5-isoquinolinyl-sulfonyl)methylamino]-3-oxo-(4-phenyl-1-piperazinyl)-propyl] phenyl ester (KN62), an inhibitor of Ca2+ /calmodulin-dependent protein kinase II, which however did not alter or only slightly reduced the relaxant response to electrical nerve stimulation in canine coronary arterial strips that is mediated via beta-adrenoceptors stimulated by norepinephrine. Nicotine-induced relaxation, mediated by nitric oxide (NO) derived from perivascular nerves, was also attenuated by KN62, whereas the response to exogenous NO was unaffected. The nicotine-induced increase in the cyclic GMP content in cerebral arteries was depressed by KN62. The neurogenic relaxation was not influenced by phorbol 12-myristate 13-acetate, an activator of protein kinase C. 8-Bromo-cyclic GMP and 8-bromo-cyclic AMP did not significantly alter the response to nerve stimulation. It is concluded that the phosphorylation pathway involving Ca2+/calmodulin-dependent protein kinase II, but not other protein kinases so far tested, appears to be involved in the function of vasodilator nerves innervating the cerebral artery.
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PMID:Effect of Ca2+/calmodulin-dependent protein kinase II inhibitors on the neurogenic cerebroarterial relaxation. 952 7


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