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 regulation of the activity of the approximately 30 pS nonselective cation channel (NSC channel) was studied by the patch-clamp technique in inside-out patches obtained from rat brown-fat cells. NSC channel activity was induced by excision; reduced redox state induced by dithiothreitol accelerated the kinetics in the excised state. The NSC channels were inhibited by the fenamates flufenamic acid and mefenamic acid but not by NS-1619 or SKF-96365. The channels were inhibited by purine nucleotides but not by polyamines. No evidence for protein kinase C, CaM kinase or protein kinase A activation of the NSC channel was obtained. NSC-channel activity was stimulated in a concentration-dependent manner by Ca2+ but the EC50 was very high (0.81 mM), in comparison to expected cytosolic Ca2+ levels. In the presence of ATP, even higher Ca2+ levels were necessary for comparable NSC-channel activation. The increase in Po was not associated with an increase in open-time constants. We conclude that although high Ca2+ levels can experimentally activate the NSC channel, a further mediatory step must probably be postulated in order to link alpha1-adrenergic stimulation to NSC-channel activation.
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PMID:Regulation of the activity of 27 pS nonselective cation channels in excised membrane patches from rat brown-fat cells. 979 52

Several kinases have been shown to phosphorylate tau protein at Ser-262, an important site involved in the regulation of the binding of tau to microtubules. In this study we compared the phosphorylation of tau at Ser-262 by CaMKII, PhK and PKA in vitro as determined by radioimmunoblots developed by the monoclonal antibody 12E8 which recognizes P-Ser-262 and P-Ser-356; and Ab-262, a polyclonal antibody which is specific to unphosphorylated Ser-262 in tau. We found that the phosphorylation at Ser-262 was several times more effective by CaMKII than PKA or PhK. Employing rat brain extract as a source of all brain kinases and KN-62, a specific inhibitor of CaMKII, we found that CaMKII accounts for approximately 45% of phosphorylation at Ser-262. Furthermore, in rat brain slices kept metabolically active in oxygenated artificial CSF, phosphorylation of tau at Ser-262 was (i) increased up to 120% in the presence of bradykinin, a CaMKII activator, and (ii) inhibited by approximately 35% in the presence of KN-62. Thus, CaMKII is a major tau Ser-262 kinase in mammalian brain.
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PMID:Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. 980 Nov 71

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed by one-third of adult rat lumbar dorsal root ganglion (DRG) neurons, many of which mediate pain sensation or cause vasodilation. The factors that regulate the developmental expression of CGRP are poorly understood. Embryonic DRG neurons initially lack CGRP. When these neurons were stimulated in culture by serum or persistent 50 mM KCl application, the same percentage of CGRP-immunoreactive (CGRP-IR) neurons developed in vitro as was seen in the adult DRG in vivo. The addition of the L-type calcium channel blockers, 5 microM nifedipine or 10 microM verapamil, dramatically decreased the proportion of CGRP-IR neurons that developed, although the N-type calcium channel blocker, 2.5 microM omega-conotoxin, was less effective. By contrast, the sodium channel blocker 1 microM tetrodotoxin had no effect on CGRP expression after depolarization. Fura-2 ratiometric imaging demonstrated that mean intracellular free calcium levels increased from 70 to 135 nM with chronic depolarization, and the addition of nifedipine inhibited that increase. Only a subpopulation of neurons had elevated calcium concentrations during chronic depolarization, and they were correlated with CGRP expression. Key signal transduction pathways were tested pharmacologically for their role in CGRP expression after depolarization; the addition of the CaM kinase inhibitor KN-62 reduced the proportion of CGRP-IR neurons to basal levels. By contrast, protein kinase A and protein kinase C were not implicated in the depolarization-induced CGRP increases. These data suggest that depolarization and the subsequent Ca2+-based signal transduction mechanisms play important roles in the de novo expression of CGRP by specific embryonic DRG neurons.
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PMID:Depolarization stimulates initial calcitonin gene-related peptide expression by embryonic sensory neurons in vitro. 980 68

Four NPY receptor subtypes have been cloned, and shown to be coupled to both Ca2+ and cAMP. However, very little is known about the downstream elements mediating NPY actions. It has recently been demonstrated in our laboratory that intrahypothalamic (i.h.t.) administration of NPY induces hypothalamic CaM kinase activity, cyclic AMP response element binding protein (CREB) phosphorylation and cyclic AMP response element (CRE) binding activity in rat hypothalamic nuclear proteins. In the present study, we have investigated whether these changes in CRE binding transcriptional factors activated by NPY results in gene regulation using a human neuroblastoma cell line (SK-N-BE2). This cell line which expresses the Y2 subtype of NPY receptors was transfected with a fusion gene containing 1.305 kb of human CRF 5' flanking region with a perfect palindromic CRE site linked to firefly luciferase gene. NPY treatment increased CaM kinase II activity, CREB phosphorylation and CRE binding in these cells. In transfected cells, luciferase activity was also increased by NPY (1.8-4-fold) within 4 h of treatment. Moreover, forskolin (7-30-fold), which stimulates cAMP production, and thapsigargin (6-8-fold), which mobilizes intracellular calcium, also increased luciferase activity within 4 h of treatment. PMA (phorbol-12-myristate-13-acetate), an activator of protein kinase-C, induced luciferase activity by 1.8-fold. NPY augmented forskolin-stimulated luciferase activity from 11- to 15-fold, but had no significant effect on thapsigargin-induced luciferase activity. These findings suggest that activation of protein kinase A (PKA) or CaM kinase leads to the induction of fusion gene. NPY treatment upregulated fusion gene expression through Ca2+ pathway in SK-N-BE2 cell line. Pretreatment with CREB antisense, but not the sense oligodeoxynucleotides, inhibited forskolin-, thapsigargin- and NPY-stimulated luciferase activity. However, CREB sense or antisense oligodeoxynucleotide treatment had no effect on PMA-stimulated luciferase activity. Furthermore, NPY induced CRE binding activity and the expression of CRE containing Y1 receptor gene in SK-N-MC cell line. These findings suggest that NPY can upregulate CRE containing reporter gene including Y1 receptor gene and NPY-induced reporter gene regulation in SK-N-BE2 cells is mediated by intracellular Ca2+ and CREB protein.
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PMID:NPY upregulates genes containing cyclic AMP response element in human neuroblastoma cell lines bearing Y1 and Y2 receptors: involvement of CREB. 980 24

Using SK-N-SH cells, we observe that muscarinic acetylcholine receptor activation by methacholine (MCh) rapidly and selectively diminishes l-NE transport capacity (Vmax) with little or no change in norepinephrine (NE) Km and without apparent effects on membrane potential monitored directly under current clamp. Over the same time frame, MCh exposure reduces the density of [3H]nisoxetine binding sites (Bmax) in intact cells but not in total membrane fractions, consistent with a loss of transport capacity mediated by sequestration of transporters rather than changes in intrinsic transport activity or protein degradation. Similar changes in NE transport and [3H]nisoxetine binding capacity are observed after phorbol ester (beta-PMA) treatment. Inhibition of PKC by antagonists and downregulation of PKC by chronic treatment with phorbol esters abolishes beta-PMA-mediated effects but produce only a partial blockade of MCh-induced effects. Neither muscarinic acetylcholine receptor nor PKC activation require extracellular Ca++ to diminish NET activity. In contrast, treatment of cells with the Ca++/ATPase antagonist, thapsigargin in Ca++-free medium, eliminates the staurosporine-insensitive component of MCh regulation. These findings were further corroborated by the ability of [1, 2-bis(o-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester application in Ca++-free medium to abolish NET regulation by MCh. Although they may contribute to basal NET expression, we could not implicate CaMKII-, PKA- or nitric oxide-linked pathways in MCh regulation. Together, these findings 1) provide evidence in support of G-protein coupled receptor-mediated regulation of catecholamine transport, 2) reveal intracellular Ca++-sensitive, PKC-dependent and -independent pathways that serve to regulate NET expression and 3) indicate that the diminished capacity for NE transport evident after mAChR and PKC activation involves a redistribution of NET protein.
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PMID:Acute regulation of norepinephrine transport: I. protein kinase C-linked muscarinic receptors influence transport capacity and transporter density in SK-N-SH cells. 980 4

Several lines of evidence suggest that the mechanism of action of antidepressant drugs (AD) involves adaptive changes occurring in intraneuronal post-receptor signal transduction cascades. Protein phosphorylation has a key role in signal transduction and was previously found to be a target in the action of AD (5-HT and/or NA reuptake blockers). Several studies showed that cAMP- and type II Ca2+/calmodulin-dependent protein kinases (PKA and CaMKII) are markedly affected by typical AD in two different and complementary cellular districts, respectively microtubules (a somatodendritic compartment) and synaptic vesicles (a presynaptic terminal compartment). In order to investigate whether the effect on protein kinases may be involved in the therapeutic action of drugs it is interesting to compare the effect of atypical AD with that of typical drugs. In this study the effect of the atypical AD S-adenosylmethionine (SAMe) was tested. Repeated (12 days) SAMe treatment induced in cerebrocortical microtubules an increase in the binding of cAMP to the RII PKA regulatory subunit and an increase in the endogenous phosphorylation of microtubule-associated protein 2, an effect resembling that of typical AD. In synaptic terminals the treatment induced an increase in the activity of CaMKII and in the endogenous phosphorylation of vesicular substrates. However, this modification was found in the cerebral cortex rather than in the hippocampus, where typical AD affect CaMKII. In addition the synapsin I level was decreased in the hippocampus and increased in the cerebral cortex, an effect not detected with typical AD.
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PMID:Modifications in brain cAMP- and calcium/calmodulin-dependent protein kinases induced by treatment with S-adenosylmethionine. 983 37

Serotonin robustly potentiated the activity of the InsP3 3-kinase in rat brainstem slices. This potentiation was mediated through activation of 5-HT2 receptors since it was only retrieved with the selective 5-HT2 agonist DOI but not with the 5-HT1A agonist 8OHDPAT. The enhancement of the InsP3 3-kinase activity by serotonin is positively modulated by pretreatment of the slices with the phosphatase inhibitor okadaic acid. Moreover, the specific CaMKII antagonists KN-62 and KN-93 dramatically reduced the serotonin-evoked increase in the InsP3 3-kinase activity. It is thus concluded that InsP3 3-kinase up-regulation occurs through activation of PLC-coupled serotoninergic receptors and requires the phosphorylation of the enzyme by the ubiquitous multimeric protein kinase CaMKII.
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PMID:Serotonin induces an increase in D-myo-inositol (1,4,5)-trisphosphate 3-kinase activity in rat brainstem slices. 983 16

The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase) mediates Ca++-induced augmentation of L-type Ca++ current (ICa); therefore it may act as a proarrhythmic signaling molecule during early afterdepolarizations (EADs) due to ICa. To investigate the hypothesis that ICa-dependent EADs are favored by CaM kinase activation EADs were induced with clofilium in isolated rabbit hearts. All EADs were rapidly terminated with ICa antagonists. Hearts were pretreated with the CaM kinase inhibitor KN-93 or the inactive analog KN-92 (0.5 microM) for 10 min before clofilium exposure. EADs were significantly suppressed by KN-93 (EADs present in 4/10 hearts) compared to KN-92 (EADs present in 10/11 hearts) (P =.024). There were no significant differences in parameters favoring EADs such as monophasic action potential duration or heart rate in KN-93- or KN-92-treated hearts. CaM kinase activity in situ increased 37% in hearts with EADs compared to hearts without EADs (P =.015). This increase in CaM kinase activity was prevented by pretreatment with KN-93. In vitro, KN-93 potently inhibited rabbit myocardial CaM kinase activity (calculated Ki </= 2.58 microM), but the inactive analog KN-92 did not (Ki > 100 microM). The actions of KN-93 and KN-92 on ICa and other repolarizing K+ currents did not explain preferential EAD suppression by KN-93. These data show a novel association between CaM kinase activation and EADs and are consistent with the hypothesis that the ICa and CaM kinase activation both contribute to EADs in this model.
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PMID:KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. 986 85

VP 4-8 as a highly potent behavioral-active metabolite of arginine-vasopressin (VP) has been studied in detail at four levels, i.e. ligand level, membrane binding level, intracellular level and nuclear level. The purpose of this chapter is to review and discuss the main results obtained from our recent pharmacological and biochemical investigations which are described as follows: 1, structure-function relationship of VP 4-8 and its analogs; 2, some characters of VP 4-8-specific binding, the distribution of the binding sites in the rat brain and the consequent effect on long-term potentiation of synaptic transmission; 3, a putative receptor-mediated signaling pathway involving second messenger IP3, immediately-early gene c-fos transcription and protein kinase PKC, CaMKII and MAPK; 4, peptide-induced enhancement of some crucial functional proteins such as calmodulin, nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF). The physiological significance of the events following VP 4-8 administration and particularly, its possible role in learning and memory processes are discussed.
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PMID:Function and molecular basis of action of vasopressin 4-8 and its analogues in rat brain. 1007 88

(a) Chronic electrostimulation of fast-twitch skeletal muscles makes them resemble slow-twitch muscles. The involvement of second-messenger cascades in this muscle reprogramming is not well understood. The goal of this study was to examine protein kinase activities and calmodulin levels as a function of the duration of electrostimulation. (b) Fast-twitch rabbit muscle was subjected to continuous low-frequency electrostimulation for 2 weeks. The extensor digitorum longus was taken and examined for calmodulin concentration and cAMP-dependent (PKA). Ca(2+)-phospholipid-dependent (PKC) and Ca(2+)-calmodulin-dependent (CaM kinase or PKB) protein kinase activities. (c) Electrostimulation for 14 days led to a significant increase in total calmodulin level and PKB activity, both rising in the cytosolic fraction. Protein kinase C translocated to the membrane fraction, although total activity did not change. (d) These changes could be related with electrostimulation-induced changes in excitation-contraction coupling.
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PMID:Effect of chronic electrostimulation of rabbit skeletal muscle on calmodulin level and protein kinase activity. 1021 62


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