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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, it has been shown that oocytes of marine nemertean worms resume meiosis and undergo germinal vesicle breakdown (GVBD) following treatment with either natural seawater (NSW), or the neurohormone serotonin (5-hydroxytryptamine or 5-HT). In this investigation of the nemerteans Cerebratulus lacteus and Cerebratulus sp., immunoblots and kinase assays were used to compare the roles of two regulatory kinases: mitogen-activated protein kinase (MAPK) and Cdc2/cyclin B (referred to as maturation promoting factor or MPF). Based on such analyses, an ERK (extracellular signal regulated kinase) type of MAPK was found to be activated concurrently with Cdc2/cyclin B during NSW- and 5-HT-induced maturation. MAPK activation occurred prior to GVBD and seemed to be controlled primarily by phosphorylation rather than de novo protein synthesis. Inhibition of MAPK signaling by U0126 was capable of delaying but not permanently blocking Cdc2/cyclin B activation and GVBD in 5-HT treated oocytes and subsets of NSW-treated oocytes. Collectively such data indicated that GVBD is not fully dependent on MAPK activation, since Cdc2/cyclin B can apparently be activated by MAPK-independent mechanism(s) in maturing nemertean oocytes.
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PMID:Germinal vesicle breakdown is not fully dependent on MAPK activation in maturing oocytes of marine nemertean worms. 1551 58

In the present work, we tested the hypothesis that serotonin (5-hydroxytryptamine = 5-HT) might activate the extracellular signal-regulated kinase (ERK) pathway in human peripheral blood mononuclear cells (PBMC). PBMC were maintained in culture for 72 hrs at 37 degrees C prior to the addition of 5-HT. Our results showed an increase in ERK activation by 5-HT with a peak effect at 30 min and maximal stimulation with 5-HT at 1microM. This activation of ERK did not occur in adherent monocytes suggesting that the effect was on lymphocytes. In addition, p38 MAP kinase was not activated under these conditions. The effect of 5-HT on ERK activation appeared to be mediated through the activation of 5-HT1A receptors since similar results were obtained with R-+-8-hydroxy-DPAT, a selective 5-HT1A receptor agonist and WAY100635, a selective 5-HT1A receptor antagonist, reversed the 5-HT and the R-+-8-hydroxy-DPAT effects. Results from Western blot analysis confirmed the presence of 5-HT1A receptors on the PBMC. A 5-HT2A antagonist, ketanserin, and a 5-HT transport inhibitor, fluoxetine, both failed to block the activation of ERK by 5-HT. Our results indicate that 5-HT activates ERK, but not p38, MAP kinase of human PBMC via a 5-HT1A receptor.
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PMID:5-HT activates ERK MAP kinase in cultured-human peripheral blood mononuclear cells via 5-HT1A receptors. 1553 May 5

The serotonin transporter (SERT) is regulated by various signaling mechanisms that may operate to maintain appropriate levels of synaptic serotonin (5-HT). We demonstrate that one of the mitogen-activated protein kinases (MAPKs), p38 MAPK, regulates SERT. Treatment of rat midbrain synaptosomes with p38 MAPK-specific inhibitors, PD169316 [4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole] or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], reduced 5-HT uptake. An additive SERT inhibition by PD169316 and beta-phorbol 12-myristate 13-acetate (beta-PMA) indicated the involvement of a protein kinase C (PKC)-independent MAPK pathway. Kinetic studies indicated a significant decrease in the transport capacity (V(max)) after PD169316 treatment of synaptosomes. Biotinylation studies showed reduced SERT proteins in the plasma membrane of synaptosomes after p38 MAPK inhibition and PKC activation. Phosphorylation studies using synaptosomes revealed decreased SERT phosphorylation by PD169316 but increased phosphorylation by beta-PMA. d-Amphetamine enhanced SERT basal phosphorylation and PD169316 blocked this effect. SERT interaction with protein phosphatase 2A catalytic subunit and syntaxin 1A decreased after PD169316 or beta-PMA treatment of synaptosomes. In synaptosomes, PKC activation but not p38 MAPK inhibition resulted in SERT redistribution from cholesterolrich lipid raft fractions to nonlipid raft fractions. The presence of phospho-p38 MAPK in synaptosomes and human embryonic kidney 293 (HEK-293) cells suggested the presence of constitutively active p38 MAPK in these preparations. Cotransfection of HEK-293 cells with SERT and a constitutively active form of MAP kinase kinase 3b(E) [MKK3b(E)] increased 5-HT transport, and RNA interference targeted to p38 MAPK inhibited 5-HT uptake, confirming the involvement of active p38 MAPK in SERT expression. Although PD169316 inhibited SERT insertion to the plasma membrane, beta-PMA increased SERT internalization in HEK-293 cells. Together, these results indicate a distinct role of p38 MAPK in SERT regulation.
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PMID:A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression. 1563 64

Tandospirone, an azapirone, is a selective serotonin(1A) (5-HT(1A)) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin. The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin, ACTH, and prolactin levels was 1.0 mg/kg (s.c.), while the minimal dose for corticosterone release was 3.0 mg/kg (s.c.). The ED(50) of tandospirone was 1.3 mg/kg for oxytocin, 1.2 mg/kg for ACTH, 3.0 mg/kg for corticosterone, and 0.24 mg/kg for prolactin. Pretreatment with the specific 5-HT(1A) receptor antagonist WAY 100,635 (0.3 mg/kg, s.c.) completely blocked the effects of tandospirone on plasma levels of oxytocin, ACTH, and corticosterone but shifted the dose-response curve for prolactin to the right. Tandospirone injection (10 mg/kg, s.c.) stimulated the MAP kinase signaling cascade, specifically the phosphorylation of p42/44 extracellular signal-regulated kinase (ERK). Western blot analysis revealed a significant increase in phosphorylated ERK (p-ERK) levels in the hypothalamic paraventricular nucleus (PVN) as well as the dorsal raphe nucleus 5 min following tandospirone injection. These increases were blocked by pretreatment with WAY 100,635 (0.3 mg/kg). The results are the first evidence that systemic 5-HT(1A) receptor agonist administration produces a rapid increase in p-ERK levels in vivo, providing further insight into the signaling mechanisms of the 5-HT(1A) receptor.
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PMID:Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo. 1565 73

Reactive oxygen species (ROS) play a critical role in cardiac hypertrophy. We have recently shown that the serotonin-degrading enzyme monoamine oxidase A (MAO A) is an important source of hydrogen peroxide in rat heart. In the present study, we investigated the potential role of hydrogen peroxide generated by MAO A in cardiomyocyte hypertrophy by serotonin. Serotonin (5 microM, 48 h) induced hypertrophy in cultured adult rat ventricular myocytes, as reflected by increased 3H-leucine incorporation (+43%, P<0.001) and total protein content (+22%, P<0.001). Serotonin also increased intracellular hydrogen peroxide and oxidative stress production, measured respectively by DCF fluorescence intensity and GSH/GSSG ratio, and promoted ERK1/2 phosphorylation (P<0.001). Serotonin effects were only partially inhibited by the 5-HT2B receptor antagonist SB 206553. In contrast, they were extensively (>80%) prevented by the amine uptake inhibitor imipramine, the MAO inhibitor pargyline and the MEK inhibitor PD 98059. Cardiomyocyte hypertrophy and ERK activation were also inhibited by decreasing intracellular ROS by adenoviral overexpression of catalase or cardiomyocytes treatment with the iron chelator deferoxamine. These data suggest that part of cardiac hypertrophic effect of serotonin requires hydrogen peroxide production by MAO A and ERK1/2 activation. This newly recognized, receptor-independent mechanism of serotonin may contribute to myocardial remodeling and failure.
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PMID:A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. 1570 74

A model was developed to examine dynamical properties of regulatory motifs correlated with different temporal domains of memory. The model represents short-, intermediate-, and long-term phases of protein kinase A (PKA) activation, which appear related to corresponding phases of facilitation of the Aplysia sensorimotor synapse. The model also represents phosphorylation of the transcription factor CREB1 by PKA and consequent induction of the immediate-early gene Aplysia ubiquitin hydrolase (Ap-uch), which is essential for long-term synaptic facilitation (LTF). Simulations suggest mechanisms responsible for differing profiles of synaptic facilitation following massed vs. spaced exposures to 5-HT, and suggest a novel regulatory motif (gated positive feedback) is important for LTF. Simulations suggest zero-order ultrasensitivity may underlie a requirement of a threshold number of exposures to 5-HT for LTF induction. The model makes predictions for the dynamics of PKA activation and Ap-uch induction when MAP kinase is activated, or when repression of Ap-uch is relieved by inhibiting the transcription factor CREB2. This model may therefore be useful for understanding processes underlying memory formation in Aplysia and other systems.
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PMID:Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in aplysia. 1571 68

Presynaptic, plasma membrane serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) clear 5-HT following vesicular release and are regulated through trafficking-dependent pathways. Recently, we provided evidence for a trafficking-independent mode of SERT regulation downstream of adenosine receptor (AR) activation that is sensitive to p38 MAPK inhibitors. Here, we probe this pathway in greater detail, demonstrating elevation of 5-HT transport by multiple p38 MAPK activators (anisomycin, H(2)O(2), and UV radiation), in parallel with p38 MAPK phosphorylation, as well as suppression of anisomycin stimulation by p38 MAPK siRNA treatments. Studies with transporter-transfected Chinese hamster ovary cells reveal that SERT stimulation is shared with the human norepinephrine transporter but not the human dopamine transporter. Saturation kinetic analyses of anisomycin-SERT activity reveal a selective reduction in 5-HT K(m) supported by a commensurate increase in 5-HT potency (K(i)) for displacing surface antagonist binding. Anisomycin treatments that stimulate SERT activity do not elevate surface SERT surface density whereas stimulation is lost with preexposure of cells to the surface-SERT inactivating reagent, 2-(trimethylammonium)ethyl methane thiosulfonate. Guanylyl cyclase (1H-(1,2,4)-oxadiazolo[4,3-a]-quinoxalin-1-one) and protein kinase G inhibitors (H8, DT-2) block AR stimulation of SERT yet fail to antagonize SERT stimulation by anisomycin. We thus place p38 MAPK activation downstream of protein kinase G in a SERT-catalytic regulatory pathway, distinct from events controlling SERT surface density. In contrast, the activity of protein phosphatase 2A inhibitors (fostriecin and calyculin A) to attenuate anisomycin stimulation of 5-HT transport suggests that protein phosphatase 2A is a critical component of the pathway responsible for p38 MAPK up-regulation of SERT catalytic activity.
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PMID:p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. 1572 87

5-Hydroxytryptamine (5-HT) has been found to elicit enhanced contractile effects in some vascular disorders. The present study was designed to examine if vascular 5-HT2A receptors are up-regulated during organ culture and if the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathways are involved. Compared with fresh rat mesenteric artery ring segments, the contractile responses to 5-HT were significantly increased in the segments cultured for 6, 24 or 48 hr (P<0.05, P<0.01, P<0.01, respectively). The 5-HT-induced contraction occurred via 5-HT2A receptors, since the selective 5-HT2A antagonist ketanserin blocked the 5-HT-induced contraction in the fresh segments with a pA2 value 9.5 (slope was 0.98 with 95% confidence intervals from 0.8 to 1.1). A similar result was obtained in the segments cultured for 24 hr with a pA2 value of 9.43 (slope=0.91 and 95% confidence intervals between 0.45 to 2.3). In addition, the enhanced 5-HT2A receptor contraction occurred with a significant increase of 5-HT2A receptor mRNA (P<0.05). Organ culture of the mesenteric artery was found to activate ERK1/2 already within 1 and 3 hr. It is likely that the ERK1/2 pathways were involved as a initial switch, since the selective ERK1/2 pathway inhibitor SB386023 abolished both up-regulation of 5-HT2A mRNA transcription and the enhanced contractile response to 5-HT. These data reveal a role of ERK1/2 in up-regulation of 5-HT2A receptors and suggest a possibility to inhibit the enhanced responses to 5-HT by inhibition of the ERK1/2 pathway.
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PMID:Enhanced transcription of contractile 5-hydroxytryptamine 2A receptors via extracellular signal-regulated kinase 1/2 after organ culture of rat mesenteric artery. 1575 10

Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.
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PMID:[Mechanisms of antidepressants and serotonin (5-HT)-induced glial cell line-derived neurotrophic factor (GDNF) releases in rat C6 gliobrastoma cells]. 1579 67

Serotonin [5-hydroxytryptamine (5-HT)] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes. Previously, it has been demonstrated that 5-HT may induce interleukin (IL)-6 expression in primary rat hippocampal astrocytes. The present study was undertaken to investigate the molecular pathways underlying this induction of IL-6 synthesis. As a model system, we used the human astrocytoma cell line U373 MG, which synthesizes IL-6 upon stimulation with various inducers. 5-HT dose- and time-dependently induced IL-6 protein synthesis. We identified several 5-HT receptors to be expressed on U373 MG cells, including the 5-HT1D, 5-HT2A, 5-HT3 and 5-HT7 receptors. In this report, we show that the 5-HT-induced IL-6 release is mediated by the 5-HT7 receptor based on several agonist/antagonists that were used. 5-HT-induced IL-6 synthesis is inhibited by the partially selective 5-HT7 receptor antagonist, pimozide, and the selective antagonist SB269970. Furthermore, IL-6 synthesis was induced by the 5-HT7 receptor agonist carboxamidotryptamin. In addition, we found p38 MAPKs and protein kinase C (PKC) epsilon to be involved in 5-HT-induced IL-6 synthesis as specific inhibitors of these enzymes (SB202190 and RO-31-8425, respectively) blocked 5-HT-induced IL-6 synthesis. Furthermore, 5-HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform. The p42/44 MAPKs, however, were not involved in 5-HT-induced IL-6 synthesis. This study shows, for the first time, a central role of 5-HT7 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells.
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PMID:Serotonin via 5-HT7 receptors activates p38 mitogen-activated protein kinase and protein kinase C epsilon resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells. 1583 14


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