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)

The activity of carnitine acetyltransferase (acetyl-CoA:L-carnitine O-acetyltransferase) was found to be at least 50-fold higher than that of choline acetyltransferase in PC12 cells. Nerve growth factor stimulated both enzymes in a parallel manner with respect to concentration of NGF and culture time. The stimulation of both enzymes was completely inhibited by 10 microM 6-thioguanine, an inhibitor of protein kinase N. Results are discussed with reference to the hypothesis that the two enzymes may be functionally related in neuronal cells.
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PMID:Stimulation of carnitine acetyltransferase in PC12 cells by nerve growth factor: relationship to choline acetyltransferase stimulation. 205 39

It is known that nerve growth factor (NGF) induces neurite outgrowth and elevation of the activity of adrenergic marker enzyme, tyrosine hydroxylase (TH) in clonal rat pheochromocytoma cells (PC12), whereas glioma-conditioned medium (GCM) induces neurite outgrowth and elevation of the activity of cholinergic marker enzyme, choline acetyltransferase (ChAT) in PC12 cells. In the previous study we have shown that retinoic acid (RA) induces specific elevation of ChAT activity and depression of TH activity without morphological differentiation (Matsuoka, I. et al., Brain Res., 502 (1989]. In the present study, we compared the effects of NGF, GCM and RA on the intracellular signalings in PC12 cells in relation to the mechanism of cholinergic differentiation. Addition of NGF, GCM or RA to the culture medium of PC12 cells caused a rapid rise in intracellular Ca2+ concentration [( Ca2+]i) reaching the level of almost 2.5-fold the resting condition within 3-18 h. Thereafter, [Ca2+]i of NGF-treated cells were decreased to the resting level within 12 h. On the other hand, [Ca2+]i of GCM-and RA-treated cells decreased to a level which was 1.8- to 2-fold the resting condition within 24-48 h and stayed at this level for up to 4-7 days. When homogenates of GCM- and RA-treated PC12 cells were incubated with [gamma-32P]ATP, phosphorylation of a protein with molecular mass of 27 kDa (27 K-protein) was specifically enhanced. The phosphorylation of the 27 K-protein was not seen in the homogenate of the NGF-treated cells. The phosphorylation of the 27 K-protein was dependent on Ca2+ and inhibited by inhibitors of Ca2+-dependent protein kinase, H-7 and W-7. Addition of H-7 and W-7 to the culture medium of PC12 cells abolished the elevation of ChAT activity specifically induced by GCM and RA. These observations suggested that the sustained increase of [Ca2+]i and Ca2+-dependent protein phosphorylation are involved in the intracellular signaling mechanism required for the cholinergic differentiation of PC12 cells induced by GCM and RA.
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PMID:Possible involvements of intracellular Ca2+ and Ca2+ -dependent protein phosphorylation in cholinergic differentiation of clonal rat pheochromocytoma cells (PC12) induced by glioma-conditioned medium and retinoic acid. 258

Choline acetyltransferase activity is barely detectable in a mutant pheochromocytoma PC12 cell line, A123.7, which is deficient in protein kinase A activity. Northern blot and polymerase chain reaction analyses showed that this mutant cell line has dramatically reduced levels of choline acetyltransferase mRNA, which correlates with the low level of enzyme activity. Transient transfection analysis was used to assess the functionality, in these cells, of an enhancer element and a cholinergic-specific repressor element derived from the human choline acetyltransferase gene. The results show that the enhancer element is inactive in the protein kinase A-deficient cell line. Cotransfection experiments with plasmids expressing the catalytic subunit of protein kinase A support this conclusion. These data indicate that protein kinase A regulates expression of the choline acetyltransferase gene at the transcriptional level by controlling the activity of an enhancer element.
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PMID:Expression of the choline acetyltransferase gene depends on protein kinase A activity. 786 Nov 80

The effects of the protein kinase inhibitor H-7 on early and delayed responses to nerve growth factor (NGF) were investigated in PC12 cells. H-7 reduced the NGF-induced expression of c-Fos in a dose-dependent manner without affecting the time course of c-Fos appearance. Conversely, H-7 potentiated delayed NGF effects, i.e., neurite outgrowth and Ca2+/phospholipid-dependent protein kinase (PKC) induction, but not choline acetyltransferase induction. Long-term treatment with NGF resulted in an increase of at least four tyrosine-phosphorylated protein bands with molecular masses between 39 and 48 kDa, which was also potentiated by H-7. In the absence of NGF, H-7 had no significant effect on c-Fos expression, tyrosine phosphorylation of the 45 kDa protein, or choline acetyltransferase activity. However, 4 days of exposure to H-7 alone induced PKC activity and tyrosine phosphorylation of the 39-kDa protein. The action of H-7 derivatives on neurite outgrowth did not correlate with their inhibition profile of cyclic nucleotide-dependent protein kinases. Down-regulation of PKC activity by prolonged exposure to phorbol ester did not completely abolish the effects of NGF and H-7 on induction of c-Fos, choline acetyltransferase activity, and neurite outgrowth, indicating that PKC-independent pathways contribute to these actions. These results suggest that additional pathway(s) sensitive to H-7 may exist, which induce immediate early gene expression and suppress neuronal differentiation of PC12 cells.
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PMID:Protein kinase inhibitor H-7 differentially affects early and delayed nerve growth factor responses in PC12 cells. 829 10

According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (betaA) directly affects neurons, leading to neurodegeneration and tau phosphorylation. In rat hippocampal culture, betaA exposure activates tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK-3beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death. To elucidate the mechanism of betaA-induced neuronal death, we searched for substrates of TPKI/GSK-3beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA in mitochondria. PDH was phosphorylated and inactivated by TPKI/GSK-3beta in vitro and also in betaA-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death. In cholinergic neurons, betaA impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by betaA-induced TPKI/GSK-3beta. Thus, TPKI/GSK-3beta regulates PDH and participates in energy metabolism and acetylcholine synthesis. These results suggest that TPKI/GSK-3beta plays a key role in the pathogenesis of Alzheimer disease.
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PMID:Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. 861 Jan 7

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

Transcription factor, cAMP response element-binding protein (CREB), which is phosphorylated by cAMP-dependent kinase via an increase in cAMP, and regulates gene transcription by binding to the cAMP response element (CRE) on target genes. We examined age-dependent alterations in the DNA-binding activity of CREB in rat brain regions, and the effects of rolipram, a cAMP-specific phosphodiesterase (PDE) inhibitor on the CRE-binding activity by electrophoretic mobility-shift assay (EMSA). A marked age-dependent decrease in the CRE-binding activity was shown in all brain regions examined, especially in the basal forebrain, the striatum and the hippocampus. Furthermore, CRE-binding activities in the basal forebrain of both young-adult and aged rats significantly increased 2 h after rolipram administration (1 mg/kg, i.p.), and the rolipram treatment recovered the decreased CRE-binding activity in the aged rats. The saturation experiment in EMSA also revealed that rolipram reversed the decrease in the maximum CRE-bindings in the basal forebrain with aging. Since the 5' upstream region of the rat choline acetyltransferase (ChAT) gene contains CRE, and ChAT-positive neurons in the basal forebrain project to the frontal cortex and the hippocampus, rolipram may exert its previously reported ameliorating effect on the age-related reductions of ChAT activities in the frontal cortex and the hippocampus by phosphorylating CREB in the basal forebrain with activation of cAMP-dependent protein kinase via inhibition of PDE.
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PMID:Alterations of cAMP response element-binding activity in the aged rat brain in response to administration of rolipram, a cAMP-specific phosphodiesterase inhibitor. 888 54

Acetylcholine has long been implicated in nocturnal phase adjustment of circadian rhythms, yet the subject remains controversial. Although the suprachiasmatic nucleus (SCN), site of the circadian clock, contains no intrinsic cholinergic somata, it receives choline acetyltransferase-immunopositive projections from basal forebrain and mesopontine tegmental nuclei that contribute to sleep and wakefulness. We have demonstrated that the SCN of inbred rats in a hypothalamic brain slice is sensitive to cholinergic phase adjustment via muscarinic receptors (mAChRs) only at night. We used this paradigm to probe the muscarinic signal transduction mechanism and the site(s) gating nocturnal responsiveness. The cholinergic agonist carbachol altered the circadian rhythm of SCN neuronal activity in a pattern closely resembling that for analogs of cGMP; nocturnal gating of clock sensitivity of each is preserved in vitro. Specific inhibitors of guanylyl cyclase (GC) and cGMP-dependent protein kinase (PKG), key elements in the cGMP signal transduction cascade, blocked phase shifts induced by carbachol. Further, carbachol administration to the SCN at night increased cGMP production and PKG activity. The carbachol-induced increase in cGMP was blocked both by atropine, an mAChR antagonist, and by LY83583, a GC inhibitor. We conclude that (1) mAChR regulation of the SCN is mediated via GC-->cGMP-->PKG, (2) nocturnal gating of this pathway is controlled by the circadian clock, and (3) a gating site is positioned downstream from cGMP. This study is among the first to identify a functional context for mAChR-cGMP coupling in the CNS.
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PMID:Coupling of muscarinic cholinergic receptors and cGMP in nocturnal regulation of the suprachiasmatic circadian clock. 898 88

A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to > 500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons.
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PMID:Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. 919 63

ChAT (choline acetyltransferase) is the enzyme responsible for acetylcholine synthesis and is specifically expressed in cholinergic neurons. To further characterize the transcriptional regulation of the hCHAT (human ChAT) gene by NGF, we examined the effects upon ChAT promoter activity of a family of transcription factors which are activated by NGF and several extracellular stimuli and encoded by immediate-early genes. These include NGFI-A (Egr1, zif268), NGFI-C (Egr2), Krox-20 and NGFI-B (Nurr77). Two fragments of the hChAT gene were used for functional analysis carrying 944 bp (P1) and 4000 bp (P1 + P2) of the 5' flanking region in front of the chloramphenicol acetyltransferase (CAT) reporter gene. They were transiently co-transfected with NGFI-A, NGFI-C, Krox-20 and NGFI-B expression vectors in NG108-15, SN6 and COS-1 cells. CAT activity after transfection of the p4000 ChAT-CAT reporter into both neuronal cell lines (NG108-15 and SN6 cells) was increased up to 5-fold in the presence of co-transfected NGFI-A and up to 5- and 12-fold after co-transfection of NGFI-C expression vector in NG108-15 and SN6 cells, respectively. In NG108-15 cells, dbcAMP excerted a strong enhancing activity on the transactivation properties of NGFI-C while this was not observed when cells were transfected with NGFI-A. These trans-activation effects were specific for neuronal cells. When NG108-15 cells were treated with dbcAMP in the presence of H89, a specific PKA inhibitor, the increase of transcriptional activity of NGFI-C was abolished, indicating that a signalling transduction mechanism through PKA plays a role in NGFI-C-induced trans-activation. Electrophoretic mobility-shift assays showed that the sequence GCCCGGGGAG (NGFRE) located 1205 bp upstream of the first coding ATG (E1) can bind NGFI-A but not NGFI-C. Several possibilities explaining the observed results are discussed. Finally, transfections of ChAT-CAT reporters including the P1 + P2 region or a minimal ChAT enhancer present in the P2 region in front of a heterologous promoter indicated the presence of a regulatory element which conferred AP2-dependent trans-activation with homologous as well as with heterologous promoter constructs.
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PMID:Transcriptional activation of human choline acetyltransferase by AP2- and NGF-induced factors. 938 76


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