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)

Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.
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PMID:Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. 1465 7

A qualitative model for the binding pocket proximal to the 3alpha-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3alpha-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3alpha-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3alpha-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.
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PMID:Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring. 1516 83

There is now considerable evidence supporting a mitogenic action of serotonin (5-HT) on vascular smooth muscle cells (SMC) that might participate in pulmonary hypertension (PH). Our previous studies have demonstrated that 5-HT-induced proliferation depends on the generation of reactive oxygen species and activation of extracellular signal-regulated kinase (ERK) 1/ERK2. Activation of Rho kinase (ROCK) in SMC also may be important in PH. We undertook the present study to assess the role of Rho A/ROCK and its possible relation to ERK1/ERK2 in 5-HT-induced pulmonary artery SMC proliferation. We found that this stimulation of SMC proliferation requires Rho A/ROCK as inhibition with Y27632, a ROCK inhibitor, or dominant negative (DN) mutant Rho A blocks 5-HT-induced proliferation, cyclin D1 expression, phosphorylation of Elk, and the DNA binding of transcription factors, Egr-1 and GATA-4. 5-HT activated ROCK, and the activation was blocked by GR 55562 and GR127935, 5-HT 1B/1D receptor antagonists, but not by serotonin transport (SERT) inhibitors. Activation of Rho kinase by 5-HT was independent of activation of ERK1/ERK2, and 5-HT activated ERK1/ERK2 independently of ROCK. Treatment of SMC with Y27632 and expression of DNRho A in cells blocked translocation of ERK1/ERK2 to the cellular nucleus. Depolymerization of actin with cytochalasin D (CD) and latrunculin B (latB) failed to block the translocation of ERK, suggesting that the actin cytoskeleton does not participate in the translocation. The studies show for the first time to our knowledge combinational action of SERT and a 5-HT receptor in SMC growth and Rho A/ROCK participation in 5-HT receptor 1B/1D-mediated mitogenesis of vascular SMCs through an effect on cytoplasmic to nuclear translocation of ERK1/ERK2.
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PMID:Rho kinase-induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin. 1529 78

A series of novel fluoroalkyl-containing tropane derivatives (6-8, 10-14, 17, and 18) were synthesized from cocaine. Novel compounds were evaluated for affinity and selectivity in competitive radioligand binding assays selective for cerebral serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters (SERT, DAT, and NET). The nortropane-fluoroalkyl esters (7, 10, 11) were most potent for SERT (K(i): 0.18, 0.24, and 0.30 nM, respectively). Tosylate esters 17 and 18, synthesized as precursors for [(18)F]-labeled, Positron Emission Tomography (PET) imaging agents, also showed high affinity for DAT.
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PMID:Synthesis and amine transporter affinities of novel phenyltropane derivatives as potential positron emission tomography (PET) imaging agents. 1548 38

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

The Trk family of receptor tyrosine kinases plays a role in synaptic plasticity and in behavioral memory in mammals. Here, we report the discovery of a Trk-like receptor, ApTrkl, in Aplysia. We show that it is expressed in the sensory neurons, the locus for synaptic facilitation, which is a cellular model for memory formation. Serotonin, the facilitatory neurotransmitter, activates ApTrkl, which, in turn, leads to activation of ERK. Finally, inhibiting the activation of ApTrkl with the Trk inhibitor K252a or using dsRNA to inhibit ApTrkl blocks the serotonin-mediated activation of ERK in the cell body, as well as the cell-wide long-term facilitation induced by 5-HT application to the cell body. Thus, transactivation of the receptor tyrosine kinase ApTrkl by serotonin is an essential step in the biochemical events leading to long-term facilitation in Aplysia.
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PMID:ApTrkl, a Trk-like receptor, mediates serotonin- dependent ERK activation and long-term facilitation in Aplysia sensory neurons. 1554 18

There is evidence to suggest that the antidepressant activity of sleep deprivation may be due to an enhancement of serotonergic and/or noradrenergic neurotransmission in brain. In the present study we examined the possibility that such changes may occur at the level of the norepinephrine (NET) and serotonin (SERT) and transporters. Rats were deprived of sleep for 96 h using the modified multiple platform method and then sacrificed for autoradiographic assessments of NET and SERT binding throughout the brain. [3H]Nisoxetine binding to the NE transporter was generally decreased in 44 of 45 areas examined, with significant reductions occurring in the anterior cingulate cortex (-16%), endopiriform n. (-18%), anterior olfactory n. (-19%), glomerular layer of olfactory bulb (-18%), ventral pallidum (-14%), medial preoptic area (-16%), retrochiasmatic/arcuate hypothalamus (-18%), anteromedial thalamic n. (-15%), and rostral raphe (-17%). In contrast, SERT binding measured with [11C]DASB showed no clear directional trends in 61 brain areas examined, but was significantly reduced in subdivisions of the anterior olfactory nucleus (-22%) and substantia nigra (-18%). Thus, sleep deprivation induced widespread decreases in NET binding, and fewer and well-localized decreases in SERT binding. Significant down-regulation in one brain region, the anterior olfactory nucleus, was observed in the case of both transporters. These results suggest that mechanisms involved in the antidepressant action of sleep deprivation may involve generalized NET down-regulation as well as decreased SERT binding in specific areas. Insofar as these changes may be associated with increased levels of serotonin (5-HT) and norepinephrine (NE) in the synapse, they suggest that sleep deprivation may share some basic mechanisms of action with several current antidepressant medications.
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PMID:Distinct effects of sleep deprivation on binding to norepinephrine and serotonin transporters in rat brain. 1569 38

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

Previous studies identified partial inhibitors of serotonin (5-HT) transporter and dopamine transporter binding. We report here on a partial inhibitor of 5-HT transporter (SERT) binding identified among a group of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine analogs (4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(2-trifluoromethyl-benzyl)-piperidine; TB-1-099). Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. beta-(4'-(125)Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures. Using rat brain membranes, TB-1-099 weakly inhibited DAT binding (K(i) = 439 nM), was inactive at NET binding ([(3)H]nisoxetine), and partially inhibited SERT binding with an extrapolated plateau ("A" value) of 20%. Similarly, TB-1-099 partially inhibited [(125)I]RTI-55 binding to hSERT with an extrapolated plateau (A value) of 14%. Upon examining the effect of increasing concentrations of TB-1-099 on the apparent K(d) and B(max) of [(125)I]RTI-55 binding to hSERT, we found that TB-1-099 decreased the B(max) in a dose-dependent manner and affected the apparent K(d) in a manner well described by a sigmoid dose-response curve. TB-1-099 increased the K(d) but not to the magnitude expected for a competitive inhibitor. In rat brain synaptosomes, TB-1-099 noncompetitively inhibited [(3)H]5-HT, but not [(3)H]dopamine, uptake. Dissociation experiments indicated that TB-1-099 promoted the rapid dissociation of a small component of [(125)I]RTI-55 binding to hSERT. Association experiments demonstrated that TB-1-099 slowed [(125)I]RTI-55 binding to hSERT in a manner unlike that of the competitive inhibitor indatraline. Viewed collectively, these results support the hypothesis that TB-1-099 allosterically modulates hSERT binding and function.
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PMID:Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) analog that allosterically modulates the serotonin transporter. 1586 May 77

The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT(1A) receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT(1A) receptors. This effect of 5-HT(1A) receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT(1A) modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT(1A) activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT(1A) activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT(1A)-NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.
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PMID:Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. 1594 77


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