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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Norepinephrine is a well known major vasoconstricting factor. Recent reports suggest that norepinephrine, in addition to acting as a vasoconstricting factor, may also play several additional roles in endothelial cells. These include: 1] induction of NO release. It has been demonstrated that a small GTP-binding protein, Rho, and its downstream effecter, Rho kinase (ROCK), negatively regulate endothelial nitric oxide synthase (eNOS) production. However, it is not known whether ROCK is directly involved in norepinephrine-induced NO release. 2] Norepinephrine is reported to induce a mitogenic effect, but whether MAPKs are involved in this process is unknown. 3] Recently, we demonstrated an increase in vascular endothelial growth factor (VEGF) mRNA/protein expression in human pheochromocytoma tissue in comparison to normal adrenomedullary tissue. Thus, it is reasonable to speculate that norepinephrine may stimulate the level of VEGF mRNA. The aim of the present study was to clarify the role of norepinephrine and related endothelial adrenoceptor systems in various pathophysiological conditions, such as hypertension and in particular pheochromocytoma, using human umbilical vein endothelial cells (HUVEC). Norepinephrine-induced RhoA attenuation, through cAMP/protein kinase A (PKA) activation coupled with beta-adrenoceptors, may lead to eNOS activation in acute conditions. Norepinephrine stimulates the production of VEGF mRNA through cAMP/PKA activation coupled with beta-adrenoceptors. Norepinephrine stimulates a mitogenic effect through ERK activation coupled with the alpha(1)-adrenoceptor. In conclusion, norepinephrine stimulates eNOS activity via RhoA attenuation, VEGF mRNA synthesis and mitogenic activity in endothelial cells. We propose that an excess of norepinephrine can lead to endothelial dysfunction due to these aforementioned processes.
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PMID:Effect of norepinephrine on RhoA, MAP kinase, proliferation and VEGF expression in human umbilical vein endothelial cells. 1707 May 16

Desipramine (DP) is a tricyclic antidepressant used for treating depression and numerous other psychiatric disorders. Recent studies have shown that DP can promote neurogenesis and improve the survival rate of hippocampal neurons. However, whether DP induces neuroprotection or promotes the differentiation of neural stem cells (NSCs) needs to be elucidated. In this study, we cultured NSCs derived from the hippocampal tissues of adult rats as an in vitro model to evaluate the modulation effect of DP on NSCs. First, we demonstrated that the expression of Bcl-2 mRNA and nestin in 2 microM DP-treated NSCs were up-regulated and detected by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The results of Western blotting and immunofluorescent study confirmed that Bcl-2 protein expression was significantly increased in Day 3 DP-treated NSCs. Using the Bcl-2 small interfering RNA (siRNA) method, our results further showed that DP protects the lipopolysaccharide (LPS)-induced apoptosis in NSCs, in part by activating the expression of Bcl-2. Furthermore, DP treatment significantly inhibited the induction of proinflammatory factor interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in the culture medium of LPS-treated NSCs mediated by Bcl-2 modulation. The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that DP significantly increased the functional production of serotonin (26+/-3.5 microM, DP-treated 96 h) and noradrenaline (50+/-8.9 microM, DP-treated 96 h) in NSCs through activation of the MAPK/ERK pathway and partially mediated by Bcl-2. In conclusion, the present results indicate that DP can increase neuroprotection ability by inhibiting the LPS-induced inflammatory process in NSCs via the modulation of Bcl-2 expression, as confirmed by the siRNA method.
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PMID:Desipramine activated Bcl-2 expression and inhibited lipopolysaccharide-induced apoptosis in hippocampus-derived adult neural stem cells. 1751 May 25

Our previous studies have shown that naloxone-induced morphine withdrawal increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity, which is dependent on a hyperactivity of noradrenergic pathways [nucleus tractus solitarius (NTS) A(2)] innervating the hypothalamic paraventricular nucleus (PVN). Short-term regulation of catecholamine biosynthesis occurs through phosphorylation of tyrosine hydroxylase (TH), which enhances enzymatic activity. In the present study, the effect of morphine withdrawal on site-specific TH phosphorylation in the PVN and NTS-A(2) was determined by quantitative blot immunolabeling and immunohistochemistry using phosphorylation state-specific antibodies. We show that naloxone-induced morphine withdrawal phosphorylates TH at Serine (Ser)-31 but not Ser40 in PVN and NTS-A(2), which is associated with both an increase in total TH immunoreactivity in NTS-A(2) and an enhanced TH activity in the PVN. In addition, we demonstrated that TH neurons phosphorylated at Ser31 coexpress c-Fos in NTS-A(2). We then tested whether pharmacological inhibition of ERK activation by ERK kinase contributes to morphine withdrawal-induced phosphorylation of TH at Ser31. We show that the ability of morphine withdrawal to stimulate phosphorylation at this seryl residue is reduced by SL327, an inhibitor of ERK(1/2) activation. These results suggest that morphine withdrawal increases noradrenaline turnover in the PVN, at least in part, via ERK(1/2)-dependent phosphorylation of TH at Ser31.
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PMID:Regulation of serine (Ser)-31 and Ser40 tyrosine hydroxylase phosphorylation during morphine withdrawal in the hypothalamic paraventricular nucleus and nucleus tractus solitarius-A2 cell group: role of ERK1/2. 1782 52

Neuronal monoamine transporters (MATs) are involved in the pathophysiology and treatment of mental health conditions such as depression, attention deficit hyperactivity disorder, substance abuse and neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. Various structural classes of compounds have been synthesized and tested in vitro for activity against transporters of three monoamine signaling molecules: noradrenaline (NET); serotonin (SERT) and dopamine (DAT). We have developed and validated a number of pharmacophore models describing the interaction of two classes of compounds with each of these three MATs. These pharmacophores explain the selectivity of binding to the MATs for various compound classes and have been used to search in silico databases for novel, potentially selective ligands. These ligands, after confirmation of their activities, will provide tools for investigating the function of MATs as well as the potential for new therapeutic agents in mental health applications. The database searches also retrieved close analogues of known MAT ligands, further validating the approach.
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PMID:Pharmacophore design and database searching for selective monoamine neurotransmitter transporter ligands. 1802 78

A 38-year-old woman with RET gene mutation presented with tumors in her thyroid and bilateral adrenal glands. I-metaiodobenzylguanidine scintigraphy revealed accumulation of the radioisotope in both adrenal glands. Both plasma adrenaline and noradrenaline levels were elevated. The circadian rhythms for plasma adrenocorticotropic hormone (ACTH) and cortisol levels were disturbed. Plasma ACTH and cortisol levels failed to be suppressed by an overnight dexamethasone test, suggesting autonomic secretion of ACTH and cortisol, although the patient had no typical Cushingoid features, hypertension, or impaired glucose tolerance. Pathological examination showed that these tumors were pheochromocytoma and thyroid medullary carcinoma, respectively, both of which highly expressed corticotropin-releasing factor, urocortin1, and urocortin3. Together with the endocrinological and pathological observations, the patient was diagnosed as multiple endocrine neoplasia type II with corticotropin-releasing factor- and urocortin-producing tumors that stimulated ACTH and glucocorticoid secretion.
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PMID:A case of multiple endocrine neoplasia type II accompanied by thyroid medullary carcinoma and pheochromocytomas expressing corticotropin-releasing factor and urocortins. 1848 Jun 60

Pheochromocytomas/paragangliomas(PHEOs/PGLs) are rare but treacherous catecholamine-producing tumors which, if overlooked or improperly treated, will almost invariably prove fatal. Patients with MEN2 PHEOs have a high incidence of paroxysmal attacks and a higher prevalence of hypertension and other cardiovascular problems than do patients with Von-Hippel-Lindau (VHL) PHEOs. Compared to measurements of deconjugated metanephrines, plasma concentrations of free metanephrines are relatively independent of renal function and therefore more suitable for diagnosis of PHEO/PGL. Recently, the focus of Positron Emission Tomography (PET) imaging for these tumors has been the localization of PHEO. Although a limited number of studies are available, [18F]-fluorodopamine ([18F]DA) PET has been found to be the best overall imaging modality in the localization of PHEO. For adrenal PHEOs, this method seems to be comparable to other functional modalities such as [18F]-fluorodopa ([18F]DOPA) PET or [123I]-metaiodobenzylguanidine ([123I]MIBG)scintigraphy. For extraadrenal PHEOs, data are limited and more extensive studies are needed. In patients with metastatic PHEO, the sensitivity of [18F]DA PET is superior to [123I]MIBG. The so called "flip-flop" imaging showing superiority of non-specific [18F] flurodeoxyglucose (FDG) PET over specific [18F]DA PET has been described in rapidly progressive, often metastatic SDHB-associated PHEOs. Whether these data reflect PHEO cell dedifferentiation (e.g. losing Norepinephrine Transporter-NET) or increased metabolic rate remains to be established.
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PMID:Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome. 1957 Jul 38

Norepinephrine (NE) amplifies the strength of descending pain inhibition, giving inhibitors of spinal NET clinical utility in the management of pain. chi-MrIA isolated from the venom of a predatory marine snail noncompetitively inhibits NET and reverses allodynia in rat models of neuropathic pain. An analogue of chi-MrIA has been found to be a suitable drug candidate. On the basis of the NMR solution structure of this related peptide, Xen2174 (3), and structure-activity relationships of analogues, a pharmacophore model for the allosteric binding of 3 to NET is proposed. It is shown that 3 interacts with NET predominantly through amino acids in the first loop, forming a tight inverse turn presenting amino acids Tyr7, Lys8, and Leu9 in an orientation allowing for high affinity interaction with NET. The second loop interacts with a large hydrophobic pocket within the transporter. Analogues based on the pharmacophore demonstrated activities that support the proposed model. On the basis of improved chemical stability and a wide therapeutic index, 3 was selected for further development and is currently in phase II clinical trials.
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PMID:chi-Conopeptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain. 1986 Apr 31

Changes in emotional state are known to alter neuronal excitability and can modify learning and memory formation. Such experience-dependent neuronal plasticity can be long-lasting and is thought to involve the regulation of gene transcription. We found that a single fear-inducing stimulus increased GluR2 (also known as Gria2) mRNA abundance and promoted synaptic incorporation of GluR2-containing AMPA receptors (AMPARs) in mouse cerebellar stellate cells. The switch in synaptic AMPAR phenotype was mediated by noradrenaline and action potential prolongation. The subsequent rise in intracellular Ca(2+) and activation of Ca(2+)-sensitive ERK/MAPK signaling triggered new GluR2 gene transcription and a switch in the synaptic AMPAR phenotype from GluR2-lacking, Ca(2+)-permeable receptors to GluR2-containing, Ca(2+)-impermeable receptors on the order of hours. The change in glutamate receptor phenotype altered synaptic efficacy in cerebellar stellate cells. Thus, a single fear-inducing stimulus can induce a long-term change in synaptic receptor phenotype and may alter the activity of an inhibitory neural network.
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PMID:A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. 2003 75

Evidence indicates that noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and plays a neuroprotective role where inflammatory events contribute to pathology. Here we examined the ability of pharmacological enhancement of central noradrenergic tone to impact upon activation of the IL-1 system in rat brain. Treatment with the noradrenaline reuptake inhibitor reboxetine combined with the alpha(2)-adrenoceptor antagonist idazoxan induced expression of IL-1beta as well as its negative regulators, IL-1 receptor antagonist (IL-1ra) and IL-1 type II receptor (IL-1RII) in rat cortex. The ability of reboxetine/idazoxan treatment to activate the IL-1 system was mediated by beta-adrenoceptors, as the aforementioned effects were blocked by the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced expression of IL-1beta, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-alpha, IL-6 or IFN-gamma were not induced by clenbuterol. Induction of IL-1beta was accompanied by activation of NFkappaB and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1beta-inducible gene CINC-1. The ability of clenbuterol to activate the IL-1 system was blocked by propranolol, and was mimicked by the highly selective beta(2)-adrenoceptor agonist formoterol. Despite the ability of clenbuterol to activate the central IL-1 system, it largely combated the neuroinflammatory response induced by systemic inflammatory stimulus (bacterial lipopolysaccharide; LPS). Specifically, whilst the ability of clenbuterol to induce expression of IL-1RII and IL-1Ra was maintained following the inflammatory challenge, its ability to induce IL-1beta was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-alpha and IL-6, the inflammatory chemokines RANTES and IP-10, the co-stimulatory molecules CD40 and ICAM-1. Thus overall, clenbuterol suppresses the innate inflammatory response in rat brain.
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PMID:Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex. 2036 87

Norepinephrine (NE) and glucocorticoids (GCs) have been shown to oppositely affect various aspects of neuronal plasticity. These findings provided the basis for the plasticity hypothesis of major depression, which suggests that the disease-related impairment in neuronal plasticity is associated with long-term increase in GCs and may be reconstituted by antidepressants and monoamines. To investigate the interaction between GCs and NE, the plasticity-relevant ERK/MAPK pathway was studied in SH-SY5Y neuroblastoma cells treated with dexamethasone (DEX), a synthetic GC, NE, or both. NE treatment activated ERK and c-Jun and increased AP-1 transcriptional activity. Although DEX had no effect, co-treatment caused a prolonged and robust activation of the ERK/AP-1 pathway beyond NE-induced activation. Co-treatment also induced hyperactivation of CREB as compared to NE activation while DEX decreased pCREB. Independent alterations of ERK and CREB suggest an upstream point of interaction. Yohimbine, an alpha(2)-adrenergic receptor (AR) antagonist, prevented the hyperactivation of the ERK/AP-1 pathway and CREB induced by co-treatment. Immunofluorescence showed that after 2h of NE treatment, beta-arrestin was co-localized with the alpha(2)-AR at the plasma membrane while following co-treatment beta-arrestin was diffused within the cell, suggesting that DEX delays AR downregulation by altering beta-arrestin translocation. These results show a novel complex interaction by which GCs augment NE-induced intracellular signaling that may be relevant to antidepressant mode of action.
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PMID:Dexamethasone enhances the norepinephrine-induced ERK/MAPK intracellular pathway possibly via dysregulation of the alpha2-adrenergic receptor: implications for antidepressant drug mechanism of action. 2060 57


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