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)

We investigated the intracellular events involved in the 3,3',5-triiodo-L-thyronine (T3)-induced accumulation in acetylcholinesterase (AChE) activity in neuroblastoma cells (neuro-2a) that overexpress the human thyroid receptor beta 1 (hTR beta 1). Treatment of these cells with T3 increased AChE activity and its mRNAs after a lag period of 24-48 h, and these levels increased through stabilization of the transcripts by T3. T3 had no effect on the transcriptional rate or processing of AChE transcripts. The protein kinase inhibitor H7 inhibited T3-induced accumulation in AChE activity and its mRNAs, whereas okadaic acid (a potent inhibitor of phosphatases 1 and 2A) potentiated the effect of T3. Okadaic acid and H7 have no effect on the binding of hTR beta 1 to T3 or the transcriptional rate of the AChE gene. Finally, treatment of cells with T3 stimulated cytosolic serine/threonine, but not tyrosine kinase, activities. The time course analysis reveals that the increase in serine/threonine activity precedes the effect of T3 on AChE mRNAs. These results suggest that activation of a serine/threonine protein kinase pathway might be a link between nuclear thyroid hormone receptor activation and stabilization of AChE mRNA.
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PMID:Thyroid hormones stabilize acetylcholinesterase mRNA in neuro-2A cells that overexpress the beta 1 thyroid receptor. 853 May 2

Using probes specific for cAMP-dependent protein kinase, we have analyzed by in situ hybridization the patterns of expression of regulatory and catalytic subunits in mouse embryos and in adult muscle. RI alpha transcripts are distributed in muscle fibers exactly as acetylcholinesterase, showing that this RNA is localized at the neuromuscular junction. The transcript levels increase upon denervation of the muscle, but the RNA remains localized, indicating a regulation pattern similar to that of the epsilon subunit of nicotinic acetylcholine receptor. RI alpha transcripts have accumulated in the muscle by day 12 of mouse embryogenesis, and localization is established by day 14, at about the time of formation of junctions. This localization is maintained throughout development and in the adult. Immunocytochemical analysis has demonstrated that RI alpha protein is also localized. In addition, RI alpha recruits C alpha protein to the junction, providing at this site the potential for local responsiveness to cAMP. PKA could be implicated in the establishment and/or maintenance of the unique pattern of gene expression occurring at the junction, or in the modulation of synaptic activity via protein phosphorylation. Embryonic skeletal muscle shows a high level of C alpha transcripts and protein throughout the fiber; the transcripts are already present by day 12 of embryogenesis, and their elevated level is maintained only through fetal life. In the adult, the C alpha hybridization signal of muscle is weak and homogeneous.
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PMID:Accumulation in fetal muscle and localization to the neuromuscular junction of cAMP-dependent protein kinase A regulatory and catalytic subunits RI alpha and C alpha. 879 65

Survival, following the addition of a cAMP analog and high K+ to the medium, of cultured fetal septal cholinergic neurons was examined after nerve growth factor (NGF) deprivation. The number of acetylcholinesterase positive cells, which had progressively grown during 11-13 d of culture with NGF (50 ng/ml), was greatly reduced following 5 d of extended culture without NGF (55% of that with NGF). The degeneration of the cholinergic neurons was markedly reduced by addition of dibutyryl cAMP (dbcAMP, 1 mM), forskolin (10 microM) or KCl (15 mM) to the medium. K252b, which blocks the survival of NGF, had no effect on the action of dbcAMP. H-8 and nifedipine inhibited the survival of dbcAMP and high KCl, respectively. These results suggest that NGF, dbcAMP and high K+ promote the survival of septal cholinergic neurons acting via the receptor tyrosine kinase, protein kinase A and a Ca(2+)-dependent mechanism, respectively.
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PMID:A cyclic AMP analog and high potassium prevent the death of cultured septal cholinergic neurons after nerve growth factor withdrawal. 882 Sep 5

One of the characteristic changes that occurs in Alzheimer's disease is the loss of acetylcholinesterase (AChE) from both cholinergic and noncholinergic neurons of the brain. However, AChE activity is increased around amyloid plaques. This increase in AChE may be of significance for therapeutic strategies using AChE inhibitors. The aim of this study was to examine the effect of amyloid beta-protein (A beta), the major component of amyloid plaques, on AChE expression. A beta peptides spanning residues 1-40 or 25-35 increased AChE activity in P19 embryonal carcinoma cells. A peptide containing a scrambled A beta(25-35) sequence did not stimulate AChE expression. To examine the possibility that the increase in AChE expression was mediated by an influx of calcium through voltage-dependent calcium channels (VDCCs), drugs acting on VDCCs were tested for their effects. Inhibitors of L-type VDCCs (diltiazem, nifedipine, and verapamil), but not N- or P- or Q-type VDCCs, resulted in a decrease in AChE expression. Agonists of L-type VDCCs (maitotoxin and S(-)-Bay K 8644) increased AChE expression. As L-type VDCCs are known to be modulated by cyclic AMP-dependent protein kinase, the effect of the adenylate cyclase activator forskolin was also examined. Forskolin stimulated AChE expression, an action that was blocked by the L-type VDCC antagonist nifedipine. The A beta(25-35)induced increase in AChE expression was mediated by an L-type VDCC, as the effect was also blocked by nifedipine. The results suggest that the increase in AChE expression around amyloid plaques could be due to a disturbance in calcium homeostasis involving the opening of L-type VDCCs.
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PMID:The amyloid beta-protein of Alzheimer's disease increases acetylcholinesterase expression by increasing intracellular calcium in embryonal carcinoma P19 cells. 928 41

Cholinergic neurotransmission in the medial pontine reticular formation (mPRF) modulates rapid eye movement (REM) sleep generation. Microinjection of cholinergic agonists and acetylcholinesterase inhibitors into the mPRF induces a REM sleep-like state, and microdialysis data reveal increased mPRF levels of acetylcholine during REM sleep. Muscarinic cholinergic receptors (mAChRs) participate in REM sleep generation, and data suggest that mAChRs of a non-M1 subtype modulate REM sleep generation. The signal transduction pathway activated by m2 and m4 mAChRs involves a pertussis toxin-sensitive G protein, adenylate cyclase (AC), adenosine 3',5'-cyclic monophosphate (cAMP), and protein kinase A (PKA). Therefore, the present study tested the hypothesis that cAMP and PKA within the mPRF modulate the carbachol-induced REM sleep-like state. To test this hypothesis, the mPRF was microinjected with compounds known to facilitate the effects of cAMP (dibutyryl cAMP and 8-bromo-cAMP), stimulate PKA (Sp-cAMP[S]), and inhibit PKA (Rp-cAMP[S]). The results showed that compounds that fostered the intracellular effects of cAMP significantly decreased cholinergic REM sleep, while having no effect on spontaneously occurring REM sleep. These data are consistent with the recent finding that within the mPRF, AC and a pertussis toxin-sensitive G protein modulate cholinergic REM sleep generation. These new data suggest a modulatory role for pontine cAMP and PKA in cholinergic REM sleep regulation.
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PMID:cAMP and protein kinase A modulate cholinergic rapid eye movement sleep generation. 936 9

Here, we report that the catalytic subunit of cAMP-dependent protein kinase (PKA) but not casein kinase II or protein kinase C phosphorylates recombinant human acetylcholinesterase (AChE) in vitro. This enhances acetylthiocholine hydrolysis up to 10-fold as compared to untreated AChE, while leaving unaffected the enzyme's affinity for this substrate and for various active and peripheral site inhibitors. Alkaline phosphatase treatment enhanced the electrophoretic migration, under denaturing conditions, of part of the AChE proteins isolated from various mammalian sources and raised the isoelectric point of some of the treated AChE molecules, indicating that part of the AChE molecules are also phosphorylated in vivo. Enhancement of acetylthiocholine hydrolysis also occurred with Torpedo AChE, which has no consensus motif for PKA phosphorylation. Further, mutating the single PKA site in human AChE (threonine-249) did not prevent this enhancement, suggesting that in both cases it was due to phosphorylation at non-consensus sites. In vivo suppression of the acetylcholine hydrolyzing activity of AChE and consequent impairment in cholinergic neurotransmission occur under exposure to both natural and pharmacological compounds, including organophosphate and carbamate insecticides and chemical warfare agents. Phosphorylation of AChE may possibly offer a rapid feedback mechanism that can compensate for impairments in cholinergic neurotransmission, modulating the hydrolytic activity of this enzyme and enabling acetylcholine hydrolysis to proceed under such challenges.
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PMID:In vitro phosphorylation of acetylcholinesterase at non-consensus protein kinase A sites enhances the rate of acetylcholine hydrolysis. 942 20

Rat pheochromocytoma PC12 cells undergo neuronal differentiation in response to nerve growth factor (NGF). The differentiation involves protein kinase cascades that include the kinases MEK and ERK, as well as activation of the transcription factors c-Jun and c-Fos. We show here, that exposure of PC12 cells to mannosylerythritol lipid (MEL), a yeast extracellular glycolipid, enhances the activity of acetylcholinesterase and interrupts the cell cycle at the G1 phase, with resulting outgrowth of neurites and partial cellular differentiation. Treatment with MEL stimulates the phosphorylation of ERK to a similar extent as treatment with NGF, although, the appearance of phosphorylated ERK is somewhat delayed. Both the MEL-induced outgrowth of neurites and the increase in the activity of acetylcholinesterase are prevented by PD98059, a specific inhibitor of MEK. Northern blotting analysis of c-jun transcripts and analysis of transcription in PC12 cells of a c-jun/CAT reporter construct demonstrated a significant increase in the rate of transcription of the c-jun gene upon treatment with MEL. The sequence elements required for the MEL-mediated activation of transcription of the c-jun gene are located between nucleotides -126 and -79 in the 5' flanking region. Our results suggest that MEL induces characteristics of neuronal differentiation in PC12 cells, with transactivation of the c-jun gene, via an ERK-related signal cascade that is partially overlapping the pathways activated in response to NGF. These results might provide the groundwork for the use of microbial extracellular glycolipids as novel reagents for the treatment of cancer cells.
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PMID:Mannosylerythritol lipid induces characteristics of neuronal differentiation in PC12 cells through an ERK-related signal cascade. 1116 72

Various proteins/enzymes obtained commercially were tested for the presence of endogenously nitrated tyrosine by Western blot analysis omitting reducing agent in the step of SDS-PAGE. Histones II-S and VIII-S, IgG, cAMP-dependent protein kinase (PKA), phosphorylase b, and phosphorylase kinase exhibited strong immunoreactive bands. Histone VI-S, glycogen synthase, lactate dehydrogenase, actin, thyroglobulin, and macroglobulin exhibited moderate immunoreactivity. Histone III-S, casein, acetyl cholinesterase, DNase I, and lipase had only traceable immunoreactivity. Whereas histone VII-S, pyruvate kinase, trypsin, pepsin, chymotrypsin, protease IV, and protease XIII, and glutathione S-transferase lacked immunoreactivity. A variation of immunoreactivity between hypertensive and normaltensive rat hearts was found in the histone-agarose fractions of crude extracts. Additionally, nitrotyrosine immunoreactivity was observed in non-mammalian organisms including Eschericia coli, Saccharomyces cerevisiae and Triticum vulgaris. Upon the treatment of 15 microM peroxynitrite (PN), strong oxidant derived from nitric oxide (NO), the apparent Km of PKA for cAMP increased from approximately 10(-8) to 10(-6) M. The results imply that the varied nitration of tyrosine residues in proteins/enzymes may occur as a post-translational modification in vivo, and such discriminative nitration may be vital in PN/NO-regulated signal transduction cascade.
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PMID:Protein nitration. 1119 83

The nerve growth factor (NGF)-potentiating effect of K vitamins on PC12D cells was investigated. Treatment of PC12D cells with vitamin K(1) or K(2) in the presence of NGF significantly enhanced the proportion of neurite-bearing cells and acetylcholinesterase activity compared with NGF treatment alone. The K vitamins-enhanced neurite outgrowth on PC12D cells was completely blocked by a protein kinase A (PKA) inhibitor or mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059, whereas a protein kinase C inhibitor chelerythrine chloride did not significantly inhibit the enhancing effect of the K vitamins. These results suggest that the K vitamins enhance neurite outgrowth via the activation of PKA and MAPK-mediated signaling pathways in PC12D cells.
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PMID:Novel effect of vitamin K(1) (phylloquinone) and vitamin K(2) (menaquinone) on promoting nerve growth factor-mediated neurite outgrowth from PC12D cells. 1191 78

The expression of acetylcholinesterase (AChE) is markedly increased during myogenic differentiation of C2C12 myoblasts to myotubes; the expression is mediated by intrinsic factor(s) during muscle differentiation. In order to analyze the molecular mechanisms regulating AChE expression during myogenic differentiation, a approximately 2.2-kb human AChE promoter tagged with a luciferase reporter gene, namely pAChE-Luc, was stably transfected into C2C12 cells. The profile of promoter-driven luciferase activity during myogenic differentiation of C2C12 myotubes was found to be similar to that of endogenous expression of AChE catalytic subunit. The increase of AChE expression was reciprocally regulated by a cAMP-dependent signaling pathway. The level of intracellular cAMP, the activity of cAMP-dependent protein kinase, the phosphorylation of cAMP-responsive element binding protein and the activity of cAMP- responsive element (CRE) were down-regulated during the myotube formation. Mutating the CRE site of human AChE promoter altered the original myogenic profile of the promoter activity and its suppressive response to cAMP. In addition, the suppressive effect of the CRE site is dependent on its location on the promoter. Therefore, our results suggest that a cAMP-dependent signaling pathway serves as a suppressive element in regulating the expression of AChE during early myogenesis.
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PMID:A cyclic AMP-dependent pathway regulates the expression of acetylcholinesterase during myogenic differentiation of C2C12 cells. 1214 Feb 95


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