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)

This study demonstrates that combined dopaminergic and cholinergic denervation of the hippocampus results in the appearance of morphologically altered, Tau reactive, apical dendrites of granule cells in the rat dentate gyrus. The denervated granule cells and their apical dendrites also display immunoreactivity to a mitogen-activated protein kinase, ERK-1, and also evidence of abnormal phosphorylation of these dendrites as revealed by SMI-31 immunoreactivity. Dopaminergic denervation alone also causes mitogen activated protein kinase reactivity without the Tau-reactive apical dendrities. These results suggest an analogy to synaptophysin loss and the appearance of dendritic threads described in Alzheimer's disease (AD), as an early stage in the formation of neurofibrillary tangles (NFT). This is the first animal model in which abnormal phosphorylation of Tau has been shown to be produced experimentally in vivo.
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PMID:Denervation induced abnormal phosphorylation in hippocampal neurons. 771 57

The Ca2+/calmodulin dependent protein kinase II (CaM kinase II) is thought to play an important part in glucose-stimulated insulin secretion. To determine which of the known subtypes (alpha, beta, gamma, delta) occur in insulin-secreting cells, we amplified all types of CaM kinase II by RT-PCR and found the beta3-, gamma-, delta2- and delta6-subtypes in RINm5F insulinoma cells. None of the other 8 delta-subtypes was present. Antibodies generated against the bacterially expressed association domain of the delta2-subtype recognized the recombinant gamma and delta-subtypes. In INS-1 and RINm5F cells, as well as freshly isolated rat islets, only a 55-kDa protein corresponding in size to the delta2-subtype expressed in NIH3T3 fibroblasts was detected. The delta2-subtype therefore appears to represent the predominant subtype of CaM kinase II present in insulin secreting cells. The enzyme was primarily associated with cytoskeletal structures, and very little was present in the soluble compartment or detergent soluble fraction in INS-1- or RINm5F-cells. An analysis of its subcellular distribution was performed by sucrose and Nycodenz density gradient fractionation of INS-1 cells and detection of CaM kinase II delta by immune blots. The enzyme codistributed with insulin used as a marker for secretory granules but not with the lighter synaptic-like microvesicles detected with an antibody against synaptophysin, plasma membranes (syntaxin 1), lysosomes (arylsulfatase), or mitochondria (cytochrome c oxidase). CaM kinase II delta2 thus is identified as the subtype associated with insulin secretory granules and is likely to be involved in insulin secretion.
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PMID:Insulinoma cells contain an isoform of Ca2+/calmodulin-dependent protein kinase II delta associated with insulin secretion vesicles. 916 51

It is an open question whether new synapses form during hippocampal LTP. Here, we show that late-phase LTP (L-LTP) is associated with a significant increase in numbers of synaptic puncta identified by synaptophysin and N-cadherin, an adhesion protein involved in synapse formation during development. During potentiation, protein levels of N-cadherin are significantly elevated and N-cadherin dimerization is enhanced. The increases in synaptic number and N-cadherin levels are dependent on cAMP-dependent protein kinase (PKA) and protein synthesis, both of which are also required for L-LTP. Blocking N-cadherin adhesion prevents the induction of L-LTP, but not the early-phase of LTP (E-LTP). Our data suggest that N-cadherin is synthesized during the induction of L-LTP and recruited to newly forming synapses. N-cadherin may play a critical role in L-LTP by holding nascent pre-and postsynaptic membranes in apposition, enabling incipient synapses to acquire function and contribute to potentiation.
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PMID:Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. 1108 98

Repeated administration of psychostimulants like methamphetamine and cocaine induce behavioral sensitization, which is recognized as an animal model for dependence and psychoses. Many previous studies have proved two major cascades play a crucial roles for molecular mechanisms underling sensitization. The first one is activation of D1 dopamine receptors by robust increase of dopamine release, followed by activation of adenylyl cyclase, increase of cyclic AMP, activation of protein kinase A (PKA) and phosphorylation of proteins by PKA. The second one is activation of NMDA receptor by enhanced release of glutamine, followed by increased intracellular Ca2+ concentration, formation of Ca2+/calmodulin complex, and phosphorylation of several proteins such as calcineurin, CaM-K II and nitric oxide synthase. Recent advanced findings on sensitization mechanisms were reviewed from three different aspects: 1) Studies using knockout mice offered quite amazing findings that D1DA-receptor-lacking mice or dopamine-transporter-lacking mice can develop sensitization and dependence, which were not consistent with the previously established hypotheses based on behavioral pharmacology. In addition, those data showed the important roles of vesicular monoamine transporter 2, 5HT1B receptors and delta FosB. 2) Research on neural-plasticity-related sensitization revealed the involvement of several molecules such as tissue plasminogen activator, arc (activity-regulated, cytoskeleton-associated), synaptophysin and stathmin. Increased expression of these genes may participate in the rearrangement of neural networks with synaptogenesis and expansion of dendrites 3) Trials to discover novel-genes-involved sensitization phenomenon using differential display or subtraction cloning found some candidate genes, mrt-1, NAC-1 and CART. Although in these areas are still in progress, accumulating findings will elucidate the details of the molecular mechanism of behavioral sensitization and dependence.
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PMID:[Advanced findings on the molecular mechanisms for behavioral sensitization to psychostimulants]. 1123 97

A fundamental difference between short-term and long-term forms of synaptic plasticity is the dependence on transcription and translation of new genes. Using organotypic cultures of hippocampal slices, we have investigated whether the modulation of synapses by brain-derived neurotrophic factor (BDNF) also requires protein synthesis. Long-term treatment of hippocampal slice cultures with BDNF increased the number of docked vesicles, but not that of reserve pool vesicles, at CA1 excitatory synapses. BDNF also increased the levels of the vesicle proteins synaptophysin, synaptobrevin, and synaptotagmin, without affecting the presynaptic membrane proteins syntaxin and SNAP-25, or the vesicle-binding protein synapsin-I. The increase in synaptophysin and synaptobrevin expression was moderate (2-fold) and occurred within 6 h after BDNF application. In contrast, synaptotagmin expression took 24 h to reach maximum levels (5-fold). The delayed increase in synaptotagmin was blocked by protein synthesis inhibitors, while the early increase in synaptophysin and synaptobrevin was not. Moreover, the BDNF-induced increase of synaptotagmin was blocked by inhibiting the cAMP/protein kinase A (PKA) pathway. However, BDNF did not activate PKA, and application of a PKA activator did not mimic the BDNF effect. Taken together, these results suggest a novel, protein synthesis-dependent form of BDNF modulation that requires cAMP gating.
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PMID:Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. 1148 92

The enhancement of synaptic exocytosis is one form of long-term potentiation (LTP) of synaptic transmission. As possible mechanisms underlying this enhancement, increases in the release probability and/or the number of release sites are suggested. To obtain direct evidence for the increase in the number of functional release sites induced by protein kinase A (PKA) cascade, we attempted to visualize functional release sites using styryl dyes, FM4-64 and FM1-43, and investigated the effects of PKA on the release sites. A PKA activator FSK increased the number of active release sites by approximately 20-30%. A direct PKA activator, Sp-cAMPS, showed the same effect, which was blocked by a PKA inhibitor, KT5720, suggesting that this effect was mediated by PKA. This PKA-dependent increase in the number of release sites requires Ca(2+) in the bath solution, and Sr(2+) can not be a substitute for Ca(2+). Since the number of functional release sites is approximately half the total number of synaptophysin-immunoreactive sites, the PKA dependent activation of silent release sites of DG neuron terminals is suggested.
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PMID:Increase in number of functional release sites by cyclic AMP-dependent protein kinase in cultured neurons isolated from hippocampal dentate gyrus. 1153 97

Metabotropic glutamate receptors (mGluRs) from group III reduce glutamate release. Because these receptors reduce cAMP levels, we explored whether this signaling pathway contributes to release inhibition caused by mGluRs with low affinity for L-2-amino-4-phosphonobutyrate (L-AP4). In biochemical experiments with the population of cerebrocortical nerve terminals we find that L-AP4 (1 mm) inhibited the Ca(2+)-dependent-evoked release of glutamate by 25%. This inhibitory effect was largely prevented by the pertussis toxin but was insensitive to inhibitors of protein kinase C bisindolylmaleimide and protein kinase A H-89. Furthermore, this inhibition was associated with reduction in N-type Ca(2+) channel activity in the absence of any detectable change in cAMP levels. In the presence of forskolin, however, L-AP4 decreased the levels of cAMP. The activation of this additional signaling pathway was very efficient in counteracting the facilitation of glutamate release induced either by forskolin or the beta-adrenergic receptor agonist isoproterenol. Imaging experiments to measure Ca(2+) dynamics in single nerve terminals showed that L-AP4 strongly reduced the Ca(2+) response in 28% of the nerve terminals. Moreover, immunochemical experiments showed that 25-35% of the nerve terminals that were immunopositive to synaptophysin were also immunoreactive to the low affinity L-AP4-sensitive mGluR7. Then, mGluR7 mediates the inhibition of glutamate release caused by 1 mm L-AP4, primarily by a strong inhibition of Ca(2+) channels, although high cAMP uncovers the receptor ability to decrease cAMP.
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PMID:The inhibition of glutamate release by metabotropic glutamate receptor 7 affects both [Ca2+]c and cAMP: evidence for a strong reduction of Ca2+ entry in single nerve terminals. 1182 90

Mammalian brain memory is hypothesized to be established through two phases; short-term plasticity, as exemplified by long-term potentiation (LTP) where pre-existing synapses change transmission efficiency, and long-lasting plasticity where new synapses are formed. This hypothesis, however, has not been verified experimentally. Using cultured hippocampal slices, we show that the repeated induction of late-phase LTP by brief applications of forskolin (FK) led to a slowly-developing long-lasting synaptogenesis, as judged from electrophysiological, cytological and ultrastructural indices. These indices include (1) field postsynaptic potential standardized by field action potential, which should represent the number of synapses per neuron; (2) the amounts of synaptic marker proteins; (3) the number of synaptophysin-immunopositive puncta; (4) the number of dendritic spines per length; (5) the density of synaptic ultrastructures; (6) ultrastructures similar to synapse perforation. Increment in these indices occurred approximately 10 days after FK-application and outlasted the following weeks. The increment depended on the times and intervals of FK-application. A biologically inert FK analogue failed to produce the similar effect. An inhibitor for cyclic AMP-dependent protein kinase (PKA) blocked the synaptogenesis. The cultured brain slice repeatedly exposed to FK should serve as a good model system for the analysis of persistent synaptogenesis possibly related to long-term memory in mammalian CNS.
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PMID:Repetitive activation of protein kinase A induces slow and persistent potentiation associated with synaptogenesis in cultured hippocampus. 1244 24

Molecular mechanisms in the development of drug abuse and dependence were reviewed by taking behavioral sensitization induced by psychostimulants like amphetamines and cocaine as a typical example. Behavioral sensitization is characterized by three main features, progressive quantitative and qualitative changes in responsiveness to the drug, very long-lastingness, and development of vulnerability to other drugs and nonspecific physical and psychological stressors, in other words, cross-sensitization. These serial changes in response to the drug during abuse must result from plastic changes in the brains of abusers. As to subcellular neurochemical mechanisms of sensitization, the activation of three main cascades is indispensable, 1) D1 dopamine (DA) receptors/PKA/phospho-34Thr-DARPP-32/PP-1 cascade activated by psychostimulant-induced enhancement of DA release in the accumbens, 2) NMDA receptors and CaM-KII activated by enhanced release of glutamate, 3) activation of MAP kinase cascade by BDNF and beta 1 subunit of G protein. These, in turn, activate several transcription factors, including delta-Fos B, and affect transcription and translation of 4th or later messengers. Finally, these result in the rearrangement of neural networks, where the tone of the A10 dopamine pathway from the ventral tegmentum area to the accumbens is strengthened, and regulation by glutamatergic afferents from the frontal cortex, amygdala and hippocampus shifts into abnormal positive regulation. As amphetamines increase expression of some plasticity-related genes (e.g. synaptophysin, stathmin and arc), synaptogenesis, neuritic sprouting and elongation must develop during behavioral sensitization. These plastic changes with structural modification of neural networks in the CNS during drug abuse could induce and reinforce psychological dependence and susceptibility to drug-induced psychoses, which become increasingly intractable.
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PMID:[Molecular biology of drug dependence and behavioral sensitization]. 1264 9

Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease (AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3beta (GSK3beta). In vivo, GSK3beta phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1-/- and PS1 knock-inM146V (KIM146V) mice and cultured cells. We show that relative levels of GSK3beta activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1-/-). Concomitant with increased GSK3beta activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysin- and syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KIM146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146V mice. Thus PS1 appears to modulate GSK3beta activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility.
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PMID:Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. 1280 90


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