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)

1. Intracellular recordings were used to study the role of metabotropic glutamate receptors (mGluRs) in modulating GABA-mediated giant depolarizing potentials (GDPs) in immature rat hippocampal CA3 neurones. 2. The mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM) reduced the frequency of GDPs. The broad-spectrum ionotropic glutamate receptor antagonist kynurenic acid (1 mM) blocked GDPs. 3. In the presence of kynurenic acid, both tetanic stimulation of the hilus or bath application of quisqualic acid (1 microM) and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 microM) induced the appearance of GDPs. These effects were antagonized by MCPG (1 mM) or L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and blocked by bicuculline (10 microM). 4. 8-Bromo-cAMP (8-Br-cAMP, 0.3 mM), 3-isobutyl-1-methylxanthine (IBMX, 200 microM) or forskolin (30 microM) mimicked the effects of mGluR agonists on GDPs. The forskolin analogue 1,9-dideoxyforskolin (30 microM), which does not activate adenylate cyclase, was ineffective. 5. Incubation of slices in the presence of the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (500 microM) or superfusion of Rp-cAMPS (20 microM) prevented the effects of forskolin or t-ACPD on GDPs. In the presence of kynurenic acid, the protein kinase C activator, phorbol 12,13-diacetate (2 microM) induced the appearance of GDPs. This effect was prevented by staurosporine (1 microM). However, staurosporine (1-3 microM) did not modify the effects of t-ACPD on GDPs. 6. It is suggested that, during development, mGluRs enhance the synchronous release of GABA, responsible for GDPs, through cAMP-dependent protein kinase.
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PMID:Cyclic AMP-dependent modulation of giant depolarizing potentials by metabotropic glutamate receptors in the rat hippocampus. 858 96

The key roles of the excitatory neurotransmitter glutamate and its second messengers, nitric oxide (NO) and cGMP, in long-term potentiation and neural plasticity are well documented. However, complex functions such as memory are likely to require long term changes in synaptic efficacy which require gene expression and protein synthesis. Here we demonstrate that the glutamate receptor agonist, N-methyl-D-aspartic acid (NMDA), nitric oxide (NO) and cGMP each repress expression of the gonadotropin-releasing hormone (GnRH) gene in the hypothalamic cell line, GT1. This repression is dependent upon signals from NMDA receptors activating NO synthase to synthesize NO. In turn NO induces guanylyl cyclase to synthesize cGMP, activating cGMP- dependent protein kinase. Repression requires elevation of calcium because it only occurs in the presence of calcium ionophore or with release of intracellular calcium. Repression also requires protein synthesis. Activation of this pathway specifically represses expression of a reporter gene containing the regulatory region of the GnRH gene in transfected GT1 cells, indicating that repression occurs at the transcriptional level. Furthermore the target for transcriptional repression is a 300 bp neuron-specific enhancer found 1.5 kb upstream of the GnRH gene which is sufficient to confer repression to a heterologous promoter. Thus the NMDA/NO/cGMP neurotransmitter signal transduction pathway controls not only synaptic function but also neuron-specific gene expression.
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PMID:NMDA and nitric oxide act through the cGMP signal transduction pathway to repress hypothalamic gonadotropin-releasing hormone gene expression. 859 37

The N-methyl-D-aspartate receptor-independent form of long-term potentiation (LTP) at hippocampal mossy fiber synapses requires presynaptic Ca(2+)-dependent activation of adenylyl cyclase. To determine whether this form of LTP might occur at other synapses, we examined cerebellar parallel fibers that, like hippocampal mossy fiber synapses, express high levels of the Ca2+/calmodulin-sensitive adenylyl cyclase I. Repetitive stimulation of parallel fibers caused a long-lasting increase in synaptic strength that was associated with a decrease in paired-pulse facilitation. Blockade of glutamate receptors did not prevent LTP induction, nor did loading of Purkinje cells with a Ca2+ chelator. LTP was occluded by forskolin-induced potentiation and blocked by the protein kinase A inhibitor Rp-8-CPT-cAMPS. These findings suggest that parallel fiber synapses express a form of LTP that is dependent on the activation of a presynaptic adenylyl cyclase and is indistinguishable from LTP at hippocampal mossy fiber synapses.
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PMID:Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. 860 97

Metabotropic glutamate receptors, nitric oxide (NO), and the signal transduction pathways of protein kinase C (PKC) and protein kinase A (PKA) can independently alter ischemic-induced neuronal cell death. We therefore examined whether the protective effects of metabotropic glutamate receptors during anoxia and NO toxicity were mediated through the cellular pathways of PKC or PKA in primary hippocampal neurons. Pretreatment with the metabotropic glutamate receptor agonists (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) 1 h before anoxia or NO exposure increased hippocampal neuronal cell survival from approximately 30 to 70%. In addition, posttreatment with 1S,3R-ACPD or L-AP4 up to 6 h following an insult attenuated anoxic- or NO-induced neurodegeneration. In contrast, treatment with L-(+)-2-amino-3-phosphonopropionic acid, an antagonist of the metabotropic glutamate receptor, did not significantly alter neuronal survival during anoxia or NO exposure. Protection by the ACPD-sensitive metabotropic receptors, such as the subtypes mGluR1 alpha, mGluR2, and mGluR5, appears to be dependent on the modulation of PKC activity. In contrast, L-AP4-sensitive metabotropic glutamate receptors, such as the subtype mGluR4, may increase neuronal survival through PKA rather than PKC. Thus, activation of specific metabotropic glutamate receptors is protective during anoxia and NO toxicity, but the signal transduction pathways mediating protection differ among the metabotropic glutamate receptor subtypes.
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PMID:Cellular mechanisms of protection by metabotropic glutamate receptors during anoxia and nitric oxide toxicity. 863 65

We have characterized the phosphorylation of the glutamate receptor subunit GluR1, using biochemical and electrophysiological techniques. GluR1 is phosphorylated on multiple sites that are all located on the C-terminus of the protein. Cyclic AMP-dependent protein kinase specifically phosphorylates SER-845 of GluR1 in transfected HEK cells and in neurons in culture. Phosphorylation of this residue results in a 40% potentiation of the peak current through GluR1 homomeric channels. In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons. These results are consistent with the recently proposed transmembrane topology models of glutamate receptors, in which the C-terminus is intracellular. In addition, the modulation of GluR1 by PKA phosphorylation of Ser-845 suggests that phosphorylation of this residue may underlie the PKA-induced potentiation of AMPA receptors in neurons.
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PMID:Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. 866 94

Studies of various forms of synaptic plasticity in the central nervous system have provided insights into the cellular and molecular mechanisms for certain types of learning and memory. Activity-induced decreases and increases in synaptic efficacy can be elicited in mammalian neurons. Long-term depression (LTD) and long-term potentiation (LTP) are two major forms of activity-dependent synaptic plasticity in the brain. LTD of excitatory synaptic transmission in the cerebellum in the most well studied form of synaptic depression. The induction of cerebellar LTD requires conjunctive activation of alpha-amino-3-hydroxy-5-methyl-4-isoxalepropionate (AMPA) receptors, metabotropic glutamate receptors (mGluRs) and L-type voltage-dependent Ca2+ channels. Several intracellular second messengers and protein kinases are critical for cerebellar LTD, including cGMP, cGMP-dependent protein kinase and protein kinase C (PKC). A novel intercellular messenger, nitric oxide (NO), is found in the cerebellum, is released durinng synaptic stimulation, and may contribute to cerebellar LTD. The expression of cerebellar LTD is mediated by postsynaptic desensitization of AMPA receptors. Recently, a form of homosynaptic LTD has been described in the CA1 region of the hippocampus. The induction of hippocampal LTD is postsynaptic. N-Methyl-D-aspartate receptors and mGluRs are important for induction of hippocampal LTD. Other intracellular and intercellular messengers, such as NO, cGMP and cAMP, might act downstream from glutamate receptors during hippocampal LTD. The expression of hippocampal LTD is likely to be in part presynaptic. While cerebellar LTD may be important for motor learning, the behavioral role of hippocampal LTD remains to be explored.
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PMID:Long-term depression: a learning-related type of synaptic plasticity in the mammalian central nervous system. 871 37

This paper presents a comprehensive survey of the pathogenesis and pathophysiology of Alzheimer's disease (AD). Two mechanisms are of etiological importance in the development of a degenerative dementing brain disease: 1. Lesions in the mitochondrial genome that are caused by free radicals. Primary degenerative AD is characterized by a tendency to acquire random lesions within mitochondrial DNA that are produced by free radicals. The consequence of these lesions is a decrease in glucose turnover and a decline in oxidative phosphorylation. Point mutations on chromosome 21 are hypothesized to increase the susceptibility of mitochondrial DNA to lesions created by free radicals. 2. Ischemic brain lesions as well as traumatic brain damage cause an increase in the release of excitotoxic amino acids (glutamate, aspartate, etc.). These neurotransmitters increase CA(+2) influx into the nerve cell and significantly lower energy production. From a pathogenetic point of view, AD is characterized by a decrease in glucose turnover in the brain. The progression of AD can be monitored by F18- deoxyglucose PET studies. This technique also allows the recognition of patients who are prone to develop AD. The actual development of a cognitive deficit is a threshold phenomenon that occurs if glucose turnover in the hippocampus or temporoparietal cortex drops below a critical level of about 40% of the level of age-matched controls. The low glucose turnover in AD causes a cholinergic deficit by decreasing the synthesis of AcCoA, which is used by choline acetyltransferase in the acetylation of choline to acetylcholine. The decrease in glucose turnover also reduces oxidative phosphorylation. The resulting decrease in ATP triggers the hyperphosphorylation of tau protein by activating protein kinase 40erk. The hyperphosphorylation leads to the development of paired helical filaments. The generation of beta amyloid and the loss of neuronal synapses are also caused by a decrease in oxidative phosphorylation, since beta amyloid precursor proteins are not inserted into the membranes of nerve cells in the absence of a sufficient amount of ATP. This results in the generation of intact beta amyloid molecules and leads to amyloidosis in the brains of patients with Alzheimer's disease.
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PMID:The significance of glucose turnover in the brain in the pathogenetic mechanisms of Alzheimer's disease. 873 75

Myofibroblasts of the lamina propria of human seminiferous tubules were studied in testes having normal or slightly reduced spermatogenesis by means of electron microscopy, confocal laser microscopy and immunocytochemistry. Myofibroblasts are large, flat individual cells braced in a network of microfibrils and collagen fibrils in the tubular wall. They are arranged in discontinuous cell layers with interposed layers of an extracellular matrix. Myofibroblasts of the lamina propria exhibit an unique cell shape with the peripheral cytoplasm split up in two or more layers. After FITC-phalloidin staining and by means of confocal laser microscopy, actin filaments of variable orientation are visible in their cytoplasm. The thickness and preferential direction of actin filaments differ in the outer and innermost cell layers. The myofibroblasts express both antigens of smooth muscle cells (alpha-smooth muscle actin, pan-actin, desmin, GB 42, smooth muscle myosin), and of connective tissue cells (vimentin, fibroblast surface protein). The variable expression of these antigens evidenced the existence of different phenotypes of myofibroblasts. Immunoreactivity for basic fibroblast growth factor and transforming growth factor beta as well as for components of the extracellular matrix indicate that these agents may be important for the phenotypic differentiation of the lamina propria cells. The detection of CNPase-and galactocerebroside-immunoreactivity in a number of lamina propria cells and some cells of the intertubular tissue gives rise to the hypothesis that components of the testicular tissue share some structural similarities with glia cells of the nervous system. Finally, immunoreactivities for the neuronal and endothelial nitric oxide synthase, soluble guanylyl cyclase, cyclic GMP, calmodulin, calcium-dependent protein kinase II and glutamate indicate that the contractility of myofibroblasts in the lamina propria of human seminiferous tubules may be in part modulated by the NO/cGMP-system.
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PMID:Myofibroblasts in the lamina propria of human semi-niferous tubules are dynamic structures of heterogeneous phenotype. 879 Aug 58

Glutamatergic neurotransmission is associated with release of arachidonic acid (AA) from membrane phospholipids of both neurons and astrocytes. Since free AA has been shown to enhance glutamate-mediated synaptic transmission, it can be postulated that glutamate release and AA formation constitute a positive feed-back mechanism for sustained excitatory neurotransmission. In the present study, we examined whether the glutamate-evoked release of AA could be modulated by peptides. Using mouse cortical neurons in primary cultures, we show that the release of AA evoked by glutamate is potentiated by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide (PACAP). This effect is mediated through the activation of PACAP I receptors. However, several arguments show that this potentiating mechanism does not involve the cAMP/PKA pathway. 1) Increasing intracellular cAMP by either cholera toxin, forskolin, or 8-Br-cAMP treatments does not affect the glutamate-evoked release of AA; 2) potentiation of the glutamate response by PACAP is not prevented by the PKA inhibitor 8-Br-Rp-cAMPS. Also, an involvement of the phospholipase C protein kinase C pathways is unlikely since inhibitors of both phospholipase C (i.e. U-73122) and protein kinase C (i.e. Ro 31-8220) do not affect the potentiation of the glutamate response by PACAP. These observations indicate an effect mediated by PACAP I receptors, which does not involve the second messenger pathways classically associated with activation of this type of receptors. Furthermore, results indicate that this potentiating mechanism mediated by PACAP I receptor acts at a level downstream of the glutamate receptor-mediated calcium influx.
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PMID:Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) potentiate the glutamate-evoked release of arachidonic acid from mouse cortical neurons. Evidence for a cAMP-independent mechanism. 879 93

A mutation directing an amino acid substitution in the conserved beta-hinge region of one of the human Cks isoforms, CksHs2, was constructed by site-directed mutagenesis. Replacement of glutamine for glutamate 63 (E63Q) was predicted to stabilize the beta-interchanged dimeric and hexameric assembly of CksHs2. However, such an effect was seen only at high, non-physiological pH. Three-dimensional structures of the E63Q hexameric mutant protein were determined to 2.6 A resolution in a P4(3)2(1)2 space group and 2.1 A in the C2 space group isostructural with wild-type, and both were shown to be virtually identical to the refined 1.7 A wild-type structure. Thus, the E63Q mutation did not alter the wild-type structure and assembly of CksHs2 but, surprisingly, disrupted the essential biological function of the protein and significantly reduced its ability to bind to cyclin-dependent kinases. The Kd of wild-type CksHs2 for CDK2 was 5.05 x 10(-8) M, whereas the affinity of the mutant protein for CDK2 was too low to allow a determination. These data, coupled with the observation that monomeric but not hexameric CksHs2 interacts with cyclin-dependent kinases, suggest that glutamine 63 is likely to be directly involved in cyclin-dependent kinase binding in vitro and in vivo.
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PMID:A mutation in the human cyclin-dependent kinase interacting protein, CksHs2, interferes with cyclin-dependent kinase binding and biological function, but preserves protein structure and assembly. 880 Feb 13


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