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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phosphatase activity. Recent understanding of synaptic plasticity mechanisms underscores important roles that these synaptic phosphoproteins play in regulating both pre- and post-synaptic functions. This review will focus on key postsynaptic phosphoproteins that have been implicated to play a role in synaptic plasticity.
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PMID:Synaptic plasticity and phosphorylation. 1690 50

The cell cycle-regulatory transcription factor E2F1 induces apoptosis of postmitotic neurons in developmental and pathological situations. E2F1 transcriptionally activates many proapoptotic genes including the cyclin-dependent protein kinase cell division cycle 2 (Cdc2). Necdin is a potent mitotic suppressor expressed predominantly in postmitotic neurons and interacts with E2F1 to suppress E2F1-mediated gene transcription. The necdin gene NDN is maternally imprinted and expressed only from the paternal allele. Deletion of the paternal NDN is implicated in the pathogenesis of Prader-Willi syndrome, a genomic imprinting-associated neurodevelopmental disorder. Here, we show that paternally expressed necdin represses E2F1-dependent cdc2 gene transcription and attenuates apoptosis of postmitotic neurons. Necdin was abundantly expressed in differentiated cerebellar granule neurons (CGNs). Neuronal activity deprivation elevated the expression of both E2F1 and Cdc2 in primary CGNs prepared from mice at postnatal day 6, whereas the necdin levels remained unchanged. In chromatin immunoprecipitation analysis, endogenous necdin was associated with the cdc2 promoter containing an E2F-binding site in activity-deprived CGNs. After activity deprivation, CGNs underwent apoptosis, which was augmented in those prepared from mice defective in the paternal Ndn allele (Ndn(+m/-p)). The levels of cdc2 mRNA, protein, and kinase activity were significantly higher in Ndn(+m/-p) CGNs than in wild-type CGNs under activity-deprived conditions. Furthermore, the populations of Cdc2-immunoreactive and apoptotic cells were increased in the cerebellum in vivo of Ndn(+m/-p) mice. These results suggest that endogenous necdin attenuates neuronal apoptosis by suppressing the E2F1-Cdc2 system.
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PMID:Necdin downregulates CDC2 expression to attenuate neuronal apoptosis. 1710 74

Neuronal development and synaptic plasticity are highly regulated processes in which protein kinases play a key role. Recently, increasing attention has been paid to a serine/threonine protein kinase called mammalian target of rapamycin (mTOR) that has well-known functions in cell proliferation and growth. In neuronal cells, mTOR is implicated in multiple processes, including transcription, ubiquitin-dependent proteolysis, and microtubule and actin dynamics, all of which are crucial for neuronal development and long-term modification of synaptic strength. The aim of this article is to present our current understanding of mTOR functions in axon guidance, dendritic tree development, formation of dendritic spines, and in several forms of long-term synaptic plasticity. We also aim to present explanation for the mTOR effects on neurons at the level of mTORregulated genes and proteins.
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PMID:The growing role of mTOR in neuronal development and plasticity. 1730 53

There is growing concern over detrimental neurologic effects to human newborns caused by increased inspired oxygen concentrations. We hypothesize that hyperoxia (FiO(2)>0.95) results in increased high-affinity Ca(2+)-ATPase activity, Ca(2+)-influx, and proapoptotic protein expression in cortical neuronal nuclei of newborn piglets. Neuronal cerebral energy metabolism was documented by determining ATP and phosphocreatine levels. Neuronal nuclear conjugated dienes and fluorescent compounds were measured as indices of lipid peroxidation. High-affinity Ca(2+)-ATPase activity and ATP-dependent Ca(2+)-influx were determined to document neuronal nuclear membrane function. Hyperoxia resulted in increases in lipid peroxidation, high-affinity Ca(2+)-ATPase activity, ATP-dependent Ca(2+)-influx, and Bax/Bcl-2 ratio in the cortical neuronal nuclei of newborn piglets. We conclude that hyperoxia results in modification of neuronal nuclear membrane function leading to increased nuclear Ca(2+)-influx, and propose that hyperoxia-induced increases in intranuclear Ca(2+) activates the Ca(2+)/calmodulin-dependent protein kinase pathway, triggering increased CREB protein-mediated apoptotic protein expression in hyperoxic neurons.
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PMID:Effect of hyperoxia on cortical neuronal nuclear function and programmed cell death mechanisms. 1740 66

Neuronal L-type calcium channels contribute to dendritic excitability and activity-dependent changes in gene expression that influence synaptic strength. Phosphorylation-mediated enhancement of L-type channels containing the CaV1.2 pore-forming subunit is promoted by A-kinase anchoring proteins (AKAPs) that target cAMP-dependent protein kinase (PKA) to the channel. Although PKA increases L-type channel activity in dendrites and dendritic spines, the mechanism of enhancement in neurons remains poorly understood. Here, we show that CaV1.2 interacts directly with AKAP79/150, which binds both PKA and the Ca2+/calmodulin-activated phosphatase calcineurin (CaN). Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional regulation of L-type current amplitude in transfected HEK293 cells and hippocampal neurons. However, anchored CaN dominantly suppresses PKA enhancement of the channel. Additionally, activation of the transcription factor NFATc4 via local Ca2+ influx through L-type channels requires AKAP79/150, suggesting that this signaling complex promotes neuronal L channel signaling to the nucleus through NFATc4.
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PMID:AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling. 1764 May 27

Nitric oxide (NO) is a gaseous intercellular messenger involved in numerous processes during development, including wiring of the nervous system. Neuronal growth cones are responsible for establishing the correct connectivity in the nervous system, but how NO might affect neuronal pathfinding is not fully understood. We have demonstrated in a previous study that local application of a NO donor, NOC-7, via micropipette onto individual growth cones from Helisoma trivolvis B5 neurons results in an increase in filopodial length, a decrease in filopodial number and an increase in the intracellular calcium concentration ([Ca(2+)](i)). Moreover, these NO-induced effects were demonstrated to be mediated via an intracellular cascade involving soluble guanylyl cyclase, protein kinase G (PKG) and cyclic adenosine diphosphate ribose (cADPR). We now demonstrate that the increase in the [Ca(2+)](i) that results from local NO application is mediated via release from ryanodine receptor (RyR)-sensitive intracellular stores. We also show that PKG and RyRs are localized within growth cones and microinjection of cADPR mimics the effects of NO, providing further support that the NO-induced effects are mediated via cADPR. Lastly, we provide evidence that calcium influx across the plasma membrane is a necessary component of the NO-induced calcium increase; however, this calcium influx is secondary to the RyR-induced calcium release from intracellular stores. This study details a signalling pathway by which NO can cause changes in growth cone morphology and thus provides a mechanism by which NO could affect neuronal wiring by acting locally on individual growth cones during the pathfinding process.
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PMID:Nitric oxide regulates growth cone filopodial dynamics via ryanodine receptor-mediated calcium release. 1771 93

Neuronal communication requires the coordinated assembly of polarized structures including axons, dendrites, and synapses. Here, we report the identification of a ubiquitin ligase mind bomb 1 (Mib1) in the postsynaptic density and the characterization of its role in neuronal morphogenesis. Expression of Mib1 inhibits neurite outgrowth in cell culture and its gene deletion enhances synaptic growth at the neuromuscular junction in Drosophila. The analysis of Mib1 interactome by mass spectrometry revealed that Mib1 primarily interacts with membrane trafficking proteins [e.g., EEA1 (early endosomal antigen 1), Rab11-interacting proteins, and SNAP25 (synaptosomal-associated protein of 25 kDa)-like protein] and cell adhesion components (e.g., catenin, coronin, dystrobrevin, and syndecan), consistent with its previously reported function in protein sorting. More interestingly, Mib1 is associated with deubiquitinating enzymes, BRCC36 and the mammalian ortholog of fat facets, and a number of kinases, such as casein kinase II, MARK (microtubule affinity regulating kinase)/PAR1, and cyclin-dependent kinase 5 (CDK5). Further characterization of the Mib1-CDK5 interaction indicated that the N-terminal domain of Mib1 directly binds to the regulatory subunit p35 of the CDK5 complex. In cell culture, Mib1 induces the relocalization of p35/CDK5 without affecting its degradation. Surprisingly, p35/CDK5 downregulates the protein level of Mib1 by its kinase activity, and completely rescues the Mib1-induced inhibitory effect on neurite morphology. p35/CDK5 also genetically interacts with Mib1 in the fly according to the rough-eye phenotype. The data strongly support that the negative interplay between Mib1 and p35/CDK5 may integrate the activities of multiple pathways during neuronal development.
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PMID:Neuronal morphogenesis is regulated by the interplay between cyclin-dependent kinase 5 and the ubiquitin ligase mind bomb 1. 1772 63

Neuronal firing patterns determine the manner of neurosecretion, the underlying mechanisms of which are poorly understood. Using supraoptic nuclei in brain slices from lactating rats, we examined the involvement of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and filamentous actin (F-actin) in burst generation by oxytocin (OT) neurons. Blocking phosphorylation of ERK1/2 (pERK1/2) decreased miniature EPSCs and blocked OT-evoked bursts, as did intracellularly loading an antibody against pERK1/2. OT (10 pM) increased cytosolic pERK1/2 close to the cell membrane within the first 5 min, subsiding by 30 min, whereas OT elicited pERK1/2 nuclear translocation in closely associated supraoptic astrocytes. The increased pERK1/2 was tightly correlated with spatiotemporal actin dynamics. In OT neurons, OT initially increased F-actin, particularly at membrane subcortical areas, and then decreased it after 30 min. Both polymerization and depolymerization of actin cytoskeleton were associated with bursts, but only polymerization facilitated OT-evoked bursts. Blocking ERK1/2 activation blocked OT-evoked actin polymerization, whereas depolymerizing F-actin increased pERK1/2 expression. These changes were further identified in vivo. In intact animals, suckling increased ERK1/2 activation in the cytosol and membrane subcortical area F-actin formation in OT neurons, whereas it increased F-actin concentration in astrocytic somata. Coimmunoprecipitation showed that suckling increased molecular interactions between pERK1/2 and actin. Finally, two different blockers of ERK1/2 kinase injected intracerebroventricularly reduced suckling-evoked milk ejections. This is the first demonstration that OT mediation of suckling-evoked bursts/milk ejections is via interactions between pERK1/2 and actin cytoskeleton.
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PMID:Interaction of extracellular signal-regulated protein kinase 1/2 with actin cytoskeleton in supraoptic oxytocin neurons and astrocytes: role in burst firing. 1807 94

Neuronal activity regulates neurogenesis and neuronal differentiation in the mammalian brain. The commencement of neurotransmitter expression establishes the neuronal phenotype and enables the formation of functional connectivity between neurons. In addition, release of neurotransmitters from differentiating neurons may modulate the behaviour of neural precursors. Here, we show that neuronal activity regulates gamma-aminobutyric acid (GABA) expression in neurons generated from stem cells of the striatum and adult subventricular zone (SVZ). Differentiating neurons display spontaneous Ca2+ events, which are voltage-gated calcium channel (VGCC) dependent. Depolarization increases both the frequency of Ca2+ transients and the amount of Ca2+ influx in differentiating neurons. We show that depolarization-dependent GABA expression is regulated by the amplitude and not by the frequency of Ca2+ influx. Brief activation of VGCCs leads to Ca2+ influx that in turn promotes a rapid expression of GABA. Depolarization-dependent GABA expression does not require changes in gene expression. Instead, it involves cAMP-dependent protein kinase (PKA) and Ca2+ and phospholipid-dependent protein kinase (PKC) signalling. Activity increases the number of glutamic acid decarboxylase (GAD) 65-immunoreactive neurons in a PKA-dependent manner, without altering the expression of GAD 65, suggesting that depolarization promotes recruitment of GAD 65 by a post-translational mechanism. In line with this, depolarization does not permanently increase the expression of GABA in neurons derived from neural stem cells of the embryonic striatum, cortex and adult SVZ. Thus, neuronal activity does not merely accelerate neuronal differentiation but it may alter the mechanism of GABA synthesis in newly generated neurons.
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PMID:Depolarization promotes GAD 65-mediated GABA synthesis by a post-translational mechanism in neural stem cell-derived neurons. 1819 May 21

The cyclin-dependent kinase cdk5 is atypically active in postmitotic neurons and enigmatic among the kinases proposed as molecular actors in neurodegeneration. We generated transgenic mice to express p25, the N-terminally truncated p35 activator of cdk5, in forebrain under tetracycline control (TET-off). Neuronal expression of p25 (p25(ON)) caused high mortality postnatally and early in life. Mortality was completely prevented by administration of doxycycline in the drinking water of pregnant dams and litters until P42, allowing us to study the action of p25 in adult mouse forebrain. Neuronal p25 triggered neurodegeneration and also microgliosis, rapidly and intensely in hippocampus and cortex. Progressive neurodegeneration was severe with marked neuron loss, causing brain atrophy (40% loss at age 5 months) with nearly complete elimination of the hippocampus. Neurodegeneration did not involve phosphorylation of protein tau or generation of amyloid peptide. Degenerating neurons did not stain for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling or activated caspase-3 but were marked by FluoroJadeB in early stages. Diseased neurons were always closely associated with activated microglia already very early in the disease process. Primary neurons derived from p25 embryos were more prone to apoptosis than wild-type neurons, and they activated microglial cells in co-culture. The inducible p25 mice present as a model for neurodegeneration in hippocampal sclerosis and neocortical degeneration, with important contributions of activated microglia.
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PMID:Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. 1820 85


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