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)

We previously demonstrated in mast cell lines RBL2H3 and FMA3 that tryptophan hydroxylase (TPH) undergoes very fast turnover driven by 26S-proteasomes [Kojima, M., Oguro, K., Sawabe, K., Iida, Y., Ikeda, R., Yamashita, A., Nakanishi, N. & Hasegawa, H. (2000) J. Biochem (Tokyo) 2000, 127, 121-127]. In the present study, we have examined an involvement of TPH phosphorylation in the rapid turnover, using non-neural TPH. The proteasome-driven degradation of TPH in living cells was accelerated by okadaic acid, a protein phosphatase inhibitor. Incorporation of 32P into a 53-kDa protein, which was judged to be TPH based on autoradiography and Western blot analysis using anti-TPH serum and purified TPH as the size marker, was observed in FMA3 cells only in the presence of both okadaic acid and MG132, inhibitors of protein phosphatase and proteasome, respectively. In a cell-free proteasome system constituted mainly of RBL2H3 cell extracts, degradation of exogenous TPH isolated from mastocytoma P-815 cells was inhibited by protein kinase inhibitors KN-62 and K252a but not by H89. Consistent with the inhibitor specificity, the same TPH was phosphorylated by exogenous Ca2+/calmodulin-dependent protein kinase II in the presence of Ca2+ and calmodulin but not by protein kinase A (catalytic subunit). TPH protein thus phosphorylated by Ca2+/calmodulin-dependent protein kinase II was digested more rapidly in the cell-free proteasome system than was the nonphosphorylated enzyme. These results indicated that the phosphorylation of TPH was a prerequisite for proteasome-driven TPH degradation.
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PMID:Proteasome-driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line. 1235 9

This article reviews technical and conceptual advances in unravelling the molecular bases of long-term potentiation (LTP), learning and memory using genetic approaches. We focus on studies aimed at testing a model suggesting that protein kinases and protein phosphatases balance each other to control synaptic strength and plasticity. We describe how gene 'knock-out' technology was initially exploited to disrupt the Ca(2+)/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) gene and how refined knock-in techniques later allowed an analysis of the role of distinct phosphorylation sites in CaMKII. Further to gene recombination, regulated gene expression using the tetracycline-controlled transactivator and reverse tetracycline-controlled transactivator systems, a powerful new means for modulating the activity of specific molecules, has been applied to CaMKIIalpha and the opposing protein phosphatase calcineurin. Together with electro-physiological and behavioural evaluation of the engineered mutant animals, these genetic methodologies have helped gain insight into the molecular mechanisms of plasticity and memory. Further technical developments are, however, awaited for an even higher level of finesse.
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PMID:Inducible molecular switches for the study of long-term potentiation. 1274 Jan 26

The strength of hippocampal synapses can be persistently increased by signals that activate Ca2+/calmodulin-dependent protein kinase II (CaMKII). This CaMKII-dependent long-term potentiation is important for hippocampal learning and memory. In this work we show that CaMKII exhibits an intriguing switch-like activation that likely is important for changes in synaptic strength. We found that autophosphorylation of CaMKII by itself showed a steep dependence on Ca2+ concentration [Hill coefficient (nH) approximately 5]. However, an even steeper Ca2+ dependence (nH approximately 8) was observed when autophosphorylation is balanced by the dephosphorylation activity of protein phosphatase 1 (PP1). This autophosphorylation-dephosphorylation switch was found to be reversible because PP1 dephosphorylates CaMKII when Ca2+ is lowered to a basal level. The switch-like response of a CaMKII-PP1 system suggests that CaMKII and PP1 may function together as a simple molecular device that specifically translates only strong Ca2+ signals into all-or-none potentiation of individual hippocampal synapses.
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PMID:An ultrasensitive Ca2+/calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling. 1292 89

Increasing evidence has suggested that the interaction between dopaminergic and glutamatergic systems in prefrontal cortex (PFC) plays an important role in normal mental functions and neuropsychiatric disorders. In this study, we examined the regulation of NMDA-type glutamate receptors by the PFC dopamine D4 receptor (one of the principal targets of antipsychotic drugs). Application of the D4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity. These results identify a mechanistic link between D4 and NMDA receptors in PFC pyramidal neurons, suggesting that D4 receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.
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PMID:Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex. 1458 14

The involvement of protein phosphatases in the activation of superoxide (O2-)- generating enzyme in human neutrophils was examined using calyculin A, an inhibitor of protein phosphatase type 1 and 2A. Calyculin A inhibited the phorbol myristate acetate (PMA)- and opsonized zymosan (OZ)-activated O2- generation by human neutrophils. This inhibitory effect of calyculin A on PMA-activated O2- generation was reversed by the addition of KT5926, a specific inhibitor of myosin light chain kinase and Ca2+/calmodulin-dependent protein kinase II. These results suggest that the addition of calyculin A may cause hyperphosphorylation of some protein(s) that plays a crucial role in the PMA-dependent activation of O2- generating enzyme, and that this protein hyperphosphorylation may be evoked by a KT5926-sensitive kinase or its downstream kinase. Whereas two-dimensional analysis involving 32P revealed that calyculin A caused the hyperphosphorylation of many proteins, KT5926 mainly reduced the calyculin A-induced hyperphosphorylation of a 67 kDa protein in activated neutrophils, suggesting that the hyperphosphorylation of the 67 kDa protein might inhibit the PMA-dependent activation of NADPH oxidase. The 67 kDa cytosolic protein was moderately phosphorylated on the addition of PMA. On the other hand, in the absence of calyculin A, KT5926 inhibited both PMA-induced O2- generation and phosphorylation of the 67 kDa protein. Amino acid sequence analysis of peptides derived from the 67 kDa protein revealed that the 67 kDa protein was identical to L-plastin, an actin-bundling protein. We conclude that optimally phosphorylated L-plastin may play some crucial role in the activation of NADPH oxidase.
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PMID:Possible involvement of optimally phosphorylated L-plastin in activation of superoxide-generating NADPH oxidase. 1476 71

Multifunctional Ca(2+)-calmodulin-dependent protein kinase (CaMKII) is a Ser/Thr protein kinase uniformly distributed within the sarcoplasmic reticulum (SR) of skeletal muscle. In fast twitch muscle, no specific substrates of CaMKII have yet been identified in nonjunctional SR. Previous electron microscopy data showed that glycogen particles containing glycogen synthase (GS) associate with SR at the I band level. Furthermore, recent evidence implicates CaMKII in regulation of glucose and glycogen metabolism. Here, we demonstrate that the glycogen- and protein phosphatase 1-targeting subunit, also known as G(M), selectively localizes to the SR membranes of rabbit skeletal muscle and that G(M) and GS co-localize at the level of the I band. We further show that G(M), GS, and PP1c assemble in a structural complex that selectively localizes to nonjunctional SR and that G(M) is phosphorylated by SR-bound CaMKII and dephosphorylated by PP1c. On the other hand, no evidence for a structural interaction between G(M) and CaMKII was obtained. Using His-tagged G(M) recombinant fragments and site-directed mutagenesis, we demonstrate that the target of CaMKII is Ser(48). Taken together, these data suggest that SR-bound CaMKII participates in the regulation of GS activity through changes in the phosphorylation state of G(M). Based on these findings, we propose that SR-bound CaMKII participates in the regulation of glycogen metabolism, under physiological conditions involving repetitive raises elevations of [Ca(2+)](i).
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PMID:Glycogen- and PP1c-targeting subunit GM is phosphorylated at Ser48 by sarcoplasmic reticulum-bound Ca2+-calmodulin protein kinase in rabbit fast twitch skeletal muscle. 1559 18

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP) is a unique protein phosphatase that specifically dephosphorylates and regulates multifunctional Ca(2+)/calmodulin-dependent protein kinases (CaMKs). To clarify the physiological significance of CaMKP, we identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and fructose bisphosphate aldolase as major binding partners of CaMKP in a soluble fraction of rat brain using the two-dimensional far-Western blotting technique, in conjunction with peptide mass fingerprinting analysis. We analyzed the affinities of these interactions. Wild type CaMKP-glutathione S-transferase (GST) associated with GAPDH in a GST pull-down assay. Deletion analysis suggested that the N-terminal side of the catalytic domain of CaMKP was responsible for the binding to GAPDH. Further, anti-CaMKP antibody coimmunoprecipitated GAPDH in a rat brain extract. GAPDH was phosphorylated by CaMKI or CaMKIV in vitro; however, when CaMKP coexisted, the phosphorylation was markedly attenuated. Under these conditions, CaMKP significantly dephosphorylated CaMKI and CaMKIV, which had been phosphorylated by CaMK kinase, whereas it did not dephosphorylate the previously phosphorylated GAPDH. The results suggest that CaMKP regulates the phosphorylation level of GAPDH in the CaMKP-GAPDH complex by dephosphorylating and deactivating CaMKs that are responsible for the phosphorylation of GAPDH.
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PMID:Identification of major Ca(2+)/calmodulin-dependent protein kinase phosphatase-binding proteins in brain: biochemical analysis of the interaction. 1568 Sep 15

Calcium influx through voltage-activated Ca(2+) channels (VACCs) plays a critical role in neurotransmission. Capsaicin application inhibits VACCs and desensitizes nociceptors. In this study, we determined the signaling mechanisms of the inhibitory effect of capsaicin on VACCs in primary sensory neurons. Whole-cell voltage clamp recordings were performed in acutely isolated rat dorsal root ganglion neurons. Capsaicin caused a profound decrease in the Ca(2+) current (I(Ca)) density in capsaicin-sensitive, but not -insensitive, dorsal root ganglion neurons. At 1 mum, capsaicin suppressed about 60% of N-, P/Q-, L-, and R-type I(Ca) density. Pretreatment with iodoresiniferatoxin, a specific transient receptor potential vanilloid type 1 (TRPV1) antagonist, or intracellular application of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid blocked the inhibitory effect of capsaicin on I(ca). However, neither W-7, a calmodulin blocker, nor KN-93, a CaMKII inhibitor, attenuated the inhibitory effect of capsaicin on I(Ca). Furthermore, intracellular dialysis of deltamethrin or cyclosporin A, the specific calcineurin (protein phosphatase 2B) inhibitors, but not okadaic acid (a selective protein phosphatase 1/protein phosphatase 2A inhibitor), abolished the effect of capsaicin on I(Ca). Interestingly, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, deltamethrin, cyclosporin A, and okadaic acid each alone significantly increased the I(Ca) density and caused a depolarizing shift in the voltage dependence of activation. Immunofluorescence labeling revealed that capsaicin induced a rapid internalization of Ca(V)2.2 channels on the membrane. Thus, this study provides novel information that VACCs are tonically modulated by the intracellular Ca(2+) level and endogenous phosphatases in sensory neurons. Stimulation of TRPV1 by capsaicin down-regulates VACCs by dephosphorylation through Ca(2+)-dependent activation of calcineurin.
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PMID:Transient receptor potential vanilloid type 1 activation down-regulates voltage-gated calcium channels through calcium-dependent calcineurin in sensory neurons. 1574 91

Many neuronal processes require gene activation by synaptically evoked Ca(2+) transients. Ca(2+)-dependent signal pathways activate some transcription factors outright, but here we report that such signals also potentiate the activation of nuclear receptors by their cognate hormone, and of CBF1 by Notch, transcription factors hitherto not thought to be Ca(2+)-responsive. This potentiation is occluded by histone deacetylase inhibition, indicating a mechanism involving inactivation of co-repressors associated with these transcription factors. Synaptic activity, acting via the nuclear Ca(2+)-dependent activation of CaM kinase IV, triggers the disruption of subnuclear domains containing class II histone deacetylases (HDACs) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a broad-specificity co-repressor which represses nuclear hormone receptors and CBF1. The sequential loss of class II HDACs and SMRT from the subnuclear domains, followed by nuclear export, is associated with disruption of SMRT interaction with its target transcription factors and sensitization of these factors to their activating signal. Counterbalancing these changes, protein phosphatase 1 promotes nuclear localization of SMRT and inactivation of nuclear receptors and CBF1. Thus, the synaptically controlled kinase-phosphatase balance of the neuron determines the efficacy of SMRT-mediated repression and the signal-responsiveness of a variety of transcription factors.
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PMID:Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness. 1577 17

Alzheimer disease (AD) and related tauopathies are all characterized histopathologically by neurofibrillary degeneration. The neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAP1 and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF/SF. The state of phosphorylation of a phosphoprotein is the function of the activities of protein kinases and as well as of protein phosphatases that regulate the level of phosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. A decrease in PP-2A activity results in the abnormal hyperphosphorylation of tau not only by decreased dephosphorylation of tau but also by stimulating the activities of tau kinases like CaMKII, PKA and MAP kinases which are regulated by PP-2A. Thus, the abnormal hyperphosphorylation can be inhibited both by inhibition of the activity/s of a tau protein kinase and as well as by restoration of the activity/s of a tau protein phosphatase. The development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to inhibit the progression of AD and related tauopathies.
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PMID:Pharmacological approaches of neurofibrillary degeneration. 1597 99


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