Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.
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PMID:Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain. 1116 17

Abnormal phosphorylation of tau is a feature of Alzheimer's disease (AD), which develops prematurely in Down syndrome (DS) patients. Cognitive impairment is also recognized as a clinical characteristic of schizophrenia, which does not appear to be associated with tau-aggregate formation. Several kinases can phosphorylate tau in cell-free assays. Here we show increased activity of mitogen-activated protein kinases (MAPKs) (including ERK1/2, SAPKs and p38) in post mortem AD and DS brains, which could not be accounted for by expression changes. In contrast, glycogen synthase kinase-3 activity (GSK-3 alpha beta) was reduced significantly. Examination of tau in AD and DS using antibodies selective for MAPK phosphorylation sites showed increased immunoreactivity. In addition, phosphorylation of S(199), reportedly a selective substrate for cyclin-dependent kinase-5 (cdk5) or GSK-3 alpha beta was only observed in AD samples, which showed a concomitant increase in the expression of p25, the enhancing cofactor for cdk5 activity. However, in schizophrenia brain, MAPK-phosphorylated tau was unchanged compared to matched controls, despite similar expression levels to those in AD. The activities of the MAPKs and GSK-3 alpha beta were also unchanged. These data demonstrate that in AD and DS, enhanced MAPK activity, which has an established role in regulating neuronal plasticity and survival, can account for irregular tau phosphorylation, and that the molecular processes involved in these neurodegenerative disorders are distinct from those in schizophrenia. These data also question the significance of GSK-3 alpha beta, as much previous work carried out in vitro has placed this kinase as a favoured candidate for involvement in the pathological phosphorylation of tau.
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PMID:Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain. 1514 5

Midlatency event-related potentials (ERPs) reflect early stages in processing of modality specific information. In humans, the auditory midlatency ERPs most investigated are the P1, N1 and P2. Abnormalities of these ERPs in neuropsychiatric disorders such as schizophrenia point to deficits in information processing at early stages. Investigations of corresponding ERPs in mice might thus permit to elucidate the molecular biology of such abnormalities. We conducted studies in mice and humans in order to establish the correspondence of midlatency ERPs in mice to the human P1, N1 and P2. We investigated their so-called recovery function-i.e. their systematic amplitude changes as a function of varying stimulus onset asynchrony (SOA). Furthermore, we explored effects of specific genetic alterations (ERK1 gene deletion Gdi1 gene deletion) on this measure. In mice, P1-like activity showed a significant recovery not present in human data. In contrast, N1-like and P2-like activity in mice demonstrated similar recovery functions as the corresponding ERPs in human subjects and could be best fitted by the same function. In addition, ERK1 gene knockout mice showed a significantly different N1 recovery function compared to wild-type mice, possibly related to enhanced memory functions in these mice. Our results indicate that midlatency ERPs in mice share some, but not all, characteristics with the human P1, N1 and P2. As in humans, N1 recovery may provide an assessment of auditory sensory memory function. Investigations of these ERPs in mice may thus permit to elucidate the abnormalities underlying deficient generation of these ERPs in neuropsychiatric disorders.
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PMID:Midlatency auditory event-related potentials in mice: comparison to midlatency auditory ERPs in humans. 1530 53

Despite a growing body of evidence demonstrating that mitogen-activated protein (MAP) kinase pathways play an important physiological role in the CNS, little is known about their role and function in various mental disorders including schizophrenia. Our previous studies have shown increased expression of several intermediates of the extracellular signal-regulated (ERK) cascade and downstream transcription targets in cerebellar vermis without any changes in mesopontine tegmentum and Brodmann's area 10 in patients with schizophrenia. Given the evidence for abnormalities in schizophrenia in a neural circuit involving the cerebellum and thalamus, the present study was conducted to examine the expression of MAP kinases extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38, as well as immediate early genes fos (c-fos and fos B) and jun (c-jun, jun B and jun D) using a Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) in postmortem thalamus from schizophrenic and control subjects. There were significant increase in ERK2, c-fos and c-jun protein and mRNA levels in thalamus of patients with schizophrenia relative to controls. No statistically significant differences were found for ERK1, Fos B, Jun B or Jun D proteins in schizophrenic and control subjects. These results taken together with our previous findings provide new evidence for selective abnormalities of distinct MAP kinases and immediate early genes c-fos and c-jun in a circuit involving the thalamus and cerebellum, which may contribute significantly to the pathophysiology of schizophrenia.
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PMID:Differential expression of mitogen-activated protein kinases and immediate early genes fos and jun in thalamus in schizophrenia. 1538 Aug 60

Serotonin 5-HT2C receptors (5-HT(2C)Rs) are almost exclusively expressed in the CNS, and implicated in disorders such as obesity, depression, and schizophrenia. The present study investigated the mechanisms governing the coupling of the 5-HT(2C)R to the extracellular signal-regulated kinases (ERKs) 1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable to those found in the brain. Using the non-RNA-edited isoform of the 5-HT(2C)R, constitutive ERK1/2 phosphorylation was observed and found to be modulated by full, partial and inverse agonists. Interestingly, agonist-directed trafficking of receptor stimulus was also observed when comparing effects on phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, whereby the agonists, [+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI) and quipazine, showed reversal of efficacy between the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other. Subsequent molecular characterization found that 5-HT-stimulated ERK1/2 phosphorylation in this cellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERK module, but is independent of both receptor- and non-receptor tyrosine kinases, phospholipase C, phosphoinositide 3-kinase, and endocytosis. Our findings underscore the potential for exploiting pathway-selective receptor states in the differential modulation of signaling pathways that play prominent roles in normal and abnormal neuronal signaling.
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PMID:Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and 2. 1593 77

The dopamine D4 receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D4 receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D4 agonist PD168077 induces c-Fos expression and extracellular signal regulated kinase (ERK) phosphorylation in the hypothalamic paraventricular nucleus (PVN), a site known to regulate proerectile activity. The selective dopamine D4 receptor antagonist A-381393 blocked both c-Fos expression and ERK1/2 phosphorylation produced by PD168077. In addition, PD168077-induced ERK1/2 phosphorylation was prevented by SL327, an inhibitor of ERK1/2 phosphorylation. Interestingly, treatment with A-381393 alone significantly reduced the amount of Fos immunoreactivity as compared to basal expression observed in vehicle-treated controls. Dopamine D4 receptor and c-Fos coexpression in the PVN was observed using double immunohistochemical labeling, suggesting that PD168077-induced signaling may result from direct dopamine D4 receptor activation. Our results demonstrate functional dopamine D4 receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and MAP kinase activation. Further, the ability of the selective dopamine D4 antagonist A-381393 alone to reduce c-Fos expression below control levels may imply the presence of a tonic dopamine D4 receptor activation under basal conditions in vivo. These findings provide additional evidence that the PVN may be a site of dopamine D4 receptor-mediated proerectile activity.
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PMID:Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. 1632 24

Antipsychotics are the drugs of choice for the treatment of schizophrenia. Besides blocking monoamine receptors, these molecules affect intracellular signaling mechanisms, resulting in long-term synaptic alterations. Western blot analysis was used to investigate the effect of long-term administration (14 days) with the typical antipsychotic haloperidol and the atypical olanzapine on the expression and phosphorylation state of extracellular signal-related kinases (ERKs) 1 and 2 (ERK1/2), proteins involved in the regulation of multiple intracellular signaling cascades. A single injection of both drugs produced an overall decrease in ERK1/2 phosphorylation in different subcellular compartments. Conversely, long-term treatment with olanzapine, but not haloperidol, increased ERK1/2 phosphorylation in the prefrontal cortex in a compartment-specific and time-dependent fashion. In fact, ERK1/2 phosphorylation was elevated in the nuclear and cytosolic fractions 2 h after the last drug administration, whereas it was enhanced only in the membrane fraction when the animals were killed 24 h after the last injection. This effect might be the result of an activation of the mitogen-activated protein kinase pathway, because the phosphorylation of extracellular signal-regulated kinase kinase 1/2 was also increased by long-term olanzapine administration. Our data demonstrate that long-term exposure to olanzapine dynamically regulates ERK1/2 phosphorylation in different subcellular compartments, revealing a novel mechanism of action for this atypical agent and pointing to temporally separated locations of signaling events mediated by these kinases after long-term olanzapine administration.
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PMID:Long-term exposure to the atypical antipsychotic olanzapine differently up-regulates extracellular signal-regulated kinases 1 and 2 phosphorylation in subcellular compartments of rat prefrontal cortex. 1639 Dec 38

Transmembrane forms of neural cell adhesion molecule (NCAM140, NCAM180(1)) are key regulators of neuronal development. The extracellular domain of NCAM can occur as a soluble protein in normal brain, and its levels are elevated in neuropsychiatric disorders, such as schizophrenia; however the mechanism of ectodomain release is obscure. Ectodomain shedding of NCAM140, releasing a fragment of 115 kD, was found to be induced in NCAM-transfected L-fibroblasts by the tyrosine phosphatase inhibitor pervanadate, but not phorbol esters. Pervanadate-induced shedding was mediated by a disintegrin metalloprotease (ADAM), regulated by ERK1/2 MAP kinase. In primary cortical neurons, NCAM was shed at high levels, and the metalloprotease inhibitor GM6001 significantly increased NCAM-dependent neurite branching and outgrowth. Moreover, NCAM-dependent neurite outgrowth and branching were inhibited in neurons isolated from a transgenic mouse model of NCAM shedding. These results suggest that regulated metalloprotease-induced ectodomain shedding of NCAM down-regulates neurite branching and neurite outgrowth. Thus, increased levels of soluble NCAM in schizophrenic brain have the potential to impair neuronal connectivity.
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PMID:Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). 1696 5

The effect of ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) on cognitive impairment in mice, previously treated with methamphetamine (METH) at a dose of 1 mg/kg for 7 days, was investigated. ZSET1446 showed a significant ameliorating effect on METH-induced impairment of recognition memory, although it had no effect on exploratory behavior. ZSET1446 (1 microg/kg) recovered the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the prefrontal cortex (PFC) of METH-treated mice. The compound increased phosphorylated ERK1/2 levels in the hippocampus but not PFC of naive mice without affecting the total ERK1/2 levels. The ameliorating effect of ZSET1446 on recognition memory in METH-treated mice was negated by pretreatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, SL327 (alpha-[amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylacetonitrile). Furthermore, the dopamine D1 receptor antagonist, SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)], blocked the ameliorating effect of ZSET1446 on METH-induced memory impairment, whereas the D2 receptor antagonist, raclopride, had no effect. These results suggest that the ameliorative effect of ZSET1446 on METH-induced memory impairment is associated with indirect activation of ERK1/2 following stimulation with dopamine D1 and NMDA receptors of the PFC. ZSET1446 would be a potential candidate for further preclinical study aimed at the treatment of cognitive deficits in Alzheimer's disease and schizophrenia, as well as METH psychosis.
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PMID:A novel azaindolizinone derivative ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2. 1709 Jul 2

Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.
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PMID:DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. 1720 67


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