Mitogen-activated protein kinases in schizophrenia

Kyosseva, Svetlana V.; Elbein, Alan D.; Griffin, W. Sue T.; Mrak, Robert E.; Lyon, Melvin; Karson, Craig N.

doi:10.1016/s0006-3223(99)00104-3

Cited by 74 publications

(49 citation statements)

References 36 publications

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“…We found increased protein levels of ERK2 and decreased protein levels of the corresponding MAP kinase phosphatase (MKP) 2, a dual specificity phosphatase that dephosphorylates both the tyrosine and threonine residues (Kyosseva et al 1999). We also found an increase in the protein levels of transcription factors Elk-1, CREB and ATF-2 in the cerebellar vermis (Kyosseva et al 2000).…”

Section: Discussionmentioning

confidence: 78%

“…In a previous study, we demonstrated increased levels of ERK2 protein in the cerebellar vermis but not in brainstem and frontal pole (Brodmann area 10) from patients with schizophrenia (Kyosseva et al 1999). We found a significant elevation of MEK and c-Raf proteins in the vermis as well (unpublished results).…”

mentioning

confidence: 81%

“…Cytosolic fractions from the cerebellum, brainstem, frontal cortex, and hippocampus were prepared as previously described (Kyosseva et al 1999). Briefly, brain tissue was homogenized in 10 mM HEPES buffer, pH 7.4, containing 1 mM EDTA, 1 mM EGTA, 2 mM sodium orthovanadate, 50 mM NAF, 10 mM sodium pyrophosphate, and 0.5% NP-40, supplemented with a cocktail of protease inhibitors (1 mM PMSF and 5 g/ ml leupeptin, aprotenin, and pepstatin).…”

Section: Preparation Of Brain Extracts and Western Blot Analysismentioning

confidence: 99%

“…Moreover, recent studies have linked the MAP kinase cascade to important brain functions, such as memory consolidation and long-term neuronal plasticity (Berman et al 1998;Blum et al 1999;Impey et al 1999). Two other classes of MAP kinases, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38, are activated by various stress stimuli, including ultraviolet irradiation, inflammatory cytokines and osmotic shock (Han et al 1994;Rouse et al 1994;Freshney et al 1994;Rosette and Karin 1996;Lewis et al 1998).In a previous study, we demonstrated increased levels of ERK2 protein in the cerebellar vermis but not in brainstem and frontal pole (Brodmann area 10) from patients with schizophrenia (Kyosseva et al 1999). We found a significant elevation of MEK and c-Raf proteins in the vermis as well (unpublished results).…”

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confidence: 95%

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Differential and Region-Specific Activation of Mitogen-Activated Protein Kinases Following Chronic Administration of Phencyclidine in Rat Brain

Kyosseva

2001

Neuropsychopharmacology

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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-JunPhencyclidine (PCP) is a hallucinogenic drug, which in normal humans can produce psychotic reactions that resemble positive, negative, and cognitive symptoms of schizophrenia (Javitt and Zukin 1991;Javitt et al. 1999). Because of these symptoms, it is suggested that PCP might be a useful drug-induced model of schizophrenia (Thornberg and Saklad 1996;Jentsch and Roth 1999;Sams-Dodd 1999).In experimental animals, PCP produces dose-dependent increases in stereotyped behavior, locomotor activity, and ataxia. Although PCP affects multiple neurotransmitters, its main site of action is through binding to the so-called PCP receptor located within the ion channel formed by the N-methyl-D-aspartate (NMDA)-type glutamate receptor (Javitt 1987;MacDonald et al. 1990;Javitt and Zukin 1991 NO . 3 hibits NMDA receptor functioning in a noncompetitive manner. There is also substantial evidence implicating NMDA dysfunction in the pathophysiology of schizophrenia and other psychiatric illnesses (Olney and Farber 1995;Coyle 1996;Krystal et al. 1999).Several lines of evidence suggest an important role for the intracellular signal transduction pathways in the regulation of brain function, and mechanism of neural plasticity in responses to stress, antidepressant treatments and drugs of abuse (Duman et al. 1994, Duman 1998. One of these signal transduction pathways is the extracellular signal-regulated kinase (ERK) cascade, a member of the mitogen-activated protein (MAP) kinase family. This pathway converts extracellular stimuli at many cell surface receptors, such as tyrosine kinases and Gprotein coupled receptors (Marshall 1994;Crespo et al. 1994;Carraway and Carraway 1995), and ion channels associated with the NMDA-type glutamate receptors (Campos-Gonzalez and Kindy 1992;Gass et al. 1993;Kurino et al. 1995;Xia et al. 1996) to intracellular signals controlling gene expression (Guan 1994).In the ERK pathway (Figure 1), Ras-GTP activates the serine/threonine kinase Raf, which in turn phosporylates and activates MEK1 and MEK2. Activated MEK, which is a dual specificity kinase, activates ERK1 and ERK2 (p44 and p42 MAP kinase) through phosphorylation on threonine and tyrosine residues. Activated ERKs are translocated to the nucleus and phosphorylate a variety of transcription factors including Elk-1, cAMP response element binding protein (CREB) and activating transcription factor (ATF). Both ERK 1 and ERK2 are highly expressed in neurons Thomas and Hunt 1993;English and Sweatt 1997;Flood et al. 1998). They can b...

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 81%

Section: Preparation Of Brain Extracts and Western Blot Analysismentioning

confidence: 99%

mentioning

confidence: 95%

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Differential and Region-Specific Activation of Mitogen-Activated Protein Kinases Following Chronic Administration of Phencyclidine in Rat Brain

Kyosseva

2001

Neuropsychopharmacology

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“…2,3 Also known as mitogenactivated protein kinase phosphatase 3 (MKP3), DUSP6 additionally plays a key role in regulating extracellular signal-regulated kinase (ERK) 1/2 pathway which is implicated in pathophysiology of major psychiatric disorders. 4,5 Although Toyota et al (2000) reported a lack of association between Japanese bipolar patients and T/G polymorphism (rs2279574, Leu114Val) in DUSP6 gene, 6 a number of recent findings strongly suggests the involvement of DUSP6 in mediating psychiatric manifestations. For example, DUSP6 mRNA increases after electroconvulsive seizure in rat brain.…”

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confidence: 99%