Differential Effects of Chronic Ethanol Treatment onN-Methyl-d-aspartate R1 Splice Variants in Fetal Cortical Neurons

Kumari, Meena

doi:10.1074/jbc.m100317200

Cited by 34 publications

(48 citation statements)

References 36 publications

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“…For example, chronic ethanol was found to increase the levels of NR2B in the forebrain but not cerebral cortex (Narita and others 2000), in contrast to other studies that found that long-term voluntary ethanol intake increases the NR2B subunit in the cortex (Henniger and others 2003) and in cortical neurons (Kumari and Ticku 1998). Five days' incubation of cortical neurons with ethanol also resulted in increased level of NR1 spliced variants containing the C2′ cassette (Kumari 2001). A more recent study suggests that the expression level of NR1, but not NR2, is altered in the rat amygdala after chronic exposure to ethanol (Floyd and others 2003).…”

Section: Ethanol and Nmdarmentioning

confidence: 92%

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Ron

2004

Neuroscientist

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One of the major targets for ethanol (alcohol) in the brain is the N-methyl-D-aspartate (NMDA) receptor, a glutamate-gated ion channel. Intriguingly, the effects of ethanol on the NMDA receptor are not homogeneous throughout the brain. This review focuses on recent studies revealing molecular mechanisms that mediate the actions of ethanol on the NMDA receptor in different brain regions via changes in NMDA receptor phosphorylation and compartmentalization. Specifically, the role of the scaffolding protein RACK1 and the regulatory protein DARPP-32 in mediating the distinct effects of ethanol is presented. KeywordsN-methyl-D-aspartate (NMDA); Ethanol; Phosphorylation; RACK1; Alcoholism is a devastating disease that affects 14 million people in the United States alone and costs society $165 billion a year. Alcoholism is defined as uncontrolled consumption of alcohol (ethanol) despite the negative consequences. The disease manifests itself or results from phenotypes such as tolerance, dependence, and withdrawal and/or craving. Considerable effort has been focused on elucidating the mechanisms that underlie the development and maintenance of alcohol addiction. Interestingly, although ethanol is a small diffusible molecule ( Fig. 1), only a defined number of targets have been identified that are altered as the result of acute or chronic exposure of neurons to ethanol (Fig. 1). Even more intriguing is the fact that ethanol affects the same targets differently in different brain regions. In this review, I will present examples of how signaling events that regulate the phosphorylation state and compartmentalization of proteins determine the activities of ethanol on the N-methyl-Daspartate (NMDA) receptor (NMDAR). Posttranslation Modification: Phosphorylation/DephosphorylationThe most common posttranslation modification is the addition of a phosphate group to the serine, threonine, or tyrosine residues of a protein substrate. This reaction, termed phosphorylation, is achieved via activation of protein kinases, which are divided into three groups: serine/threonine kinases, tyrosine kinases, and dual-specificity kinases, which are able to phosphorylate all three residues. The opposite reaction, in which a phosphate group is removed from a protein (dephosphorylation), is performed by either serine/threonine or tyrosine phosphatases. Receptor kinases and phosphatases are integral parts of the plasma membrane, whereas nonreceptor kinases and phosphatases reside intracellularly, with their subcellular compartmentalization determined in large part by protein-lipid or protein-protein interactions, as will be discussed in sections 3 and 6. Kinases and phosphatases are specifically Address correspondence to: Dorit Ron, Ernest Gallo Center, 5858 Horton St., Suite 200, Emeryville,.. NIH Public Access Author ManuscriptNeuroscientist. Author manuscript; available in PMC 2006 February 7. Published in final edited form as:Neuroscientist. 2004 August ; 10(4): 325-336. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ...

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Section: Ethanol and Nmdarmentioning

confidence: 92%

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Ron

2004

Neuroscientist

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“…Interestingly, another psychoactive substance, ethanol, has been reported to cause selective changes in the expression of exon 5-containing Nmethyl-D-aspartate NR1 splice variants in mouse fetal cortical neurons although the regulatory signals for the differential effects have not yet been identified. 33 Repeated MAP treatment results in an increase in the basal levels of the neocortical mrt1b mRNA at 2 and 3 weeks of withdrawal while a rapid and transient augmentation of the gene expression occurs after acute MAP administration. These data indicate that the repeated MAP-induced increase might be a long-lasting phenomenon and regulation of mrt1 transcription could be modified during or after the repeated treatment.…”

Section: Discussionmentioning

confidence: 99%

A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex

et al. 2003

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Single or repeated exposure to psychostimulants such as amphetamines and cocaine after postnatal week 3 leads to an enduring enhancement in the psychotomimetic responses elicited by a subsequent challenge of a stimulant in rodents. This behavioral sensitization phenomenon has been considered to be the neural consequences of stimulant-induced alterations in gene expression in the brain after a critical period of postnatal development. Using a differential cloning technique, RNA arbitrarily primed PCR, we have now identified from the rat neocortex a novel and developmentally regulated methamphetamine (MAP)-inducible gene mrt1 (MAP responsive transcript 1). mrt1 encodes two major types of PDZ-and PX-domains containing proteins of approximately 62 kDa in size with different carboxy termini, Mrt1a and Mrt1b. The mrt1 mRNAs for Mrt1a, mrt1a, and for Mrt1b, mrt1b, are predominantly expressed in various brain regions and the testes, respectively. Acute MAP injection upregulated mrt1b expression in the neocortex after postnatal week 3 in a D1 receptor antagonist-sensitive manner without affecting mrt1a expression. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to change the mrt1b transcript levels. Moreover, repeated daily treatment of MAP, but not MAP plus D1 antagonist, for 5 days caused an augmentation of the basal expression of mrt1b 2 and 3 weeks after the drug discontinuation. These late-developing, cocaine-crossreactive, D1 antagonist-sensitive and long-term regulations of mrt1b by MAP are similar to the pharmacological profiles of stimulant-induced behavioral sensitization, and therefore may be associated with the initiation and/or maintenance of the long-term neuronal adaptation.

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“…was performed as described (Kumari, 2001) to examine the effect of chronic alcohol treatment on the polypeptide levels of (i) NMDA R1 subunit of the NMDA receptor in the hippocampus and cerebral cortex and (ii) Cyp 2E1 apoprotein in liver. For NMDA R1 analysis, a known amount of tissue lysate (S1 fraction) (5 μg) from control and alcoholexposed cerebral cortices or hippocampi (n = 6) and protein standards were separated on 7.5% SDS-PAGE.…”

Section: Western Blot Analysismentioning

confidence: 99%

Supplementing the liquid alcohol diet with chow enhances alcohol intake in C57 BL/6 mice

Anji

2008

Drug and Alcohol Dependence

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Background-Administration of alcohol-containing liquid diet is associated with body weight loss in rodents.Aim-of this study was to modify the alcohol-containing liquid diet paradigm to reduce the body weight loss in mice during the alcohol treatment period.Methods-Two sets of animals (Chow and No Chow groups) were exposed to chronic alcohol with a step-wise increase of alcohol in the diet. One set of control and alcohol exposed animals (Chow group) received chow during alcohol treatment. Food intake and body weight was measured every 24h. Level of intoxication was determined by measuring blood alcohol levels. Alcohol dependence of mice was determined by handling-induced convulsions (HIC) scoring. Chronic alcohol-mediated effects on brain and liver were examined.Results-Body weight loss was attenuated in chronic alcohol exposed mice in Chow group as compared to No Chow group. Chow group mice consumed higher amounts of alcohol diet resulting in higher blood alcohol levels. Brain NMDAR1 protein levels and liver Cyp2E1 levels were significantly enhanced in chronic alcohol-exposed mice in Chow and No Chow groups suggesting that known medical consequences of alcohol are not interfered with in our modified alcohol treatment paradigm. HIC in Chow and No Chow group mice peaked between 3h and 5h after alcohol withdrawal. However, the severity of alcohol withdrawal was greater in Chow group mice.Conclusions-Supplementing alcohol diet with chow not only attenuated body weight loss associated with alcohol intake in mice but also resulted in higher consumption of alcohol diet and higher blood alcohol levels. KeywordsC57 BL/6 mice; chronic alcohol treatment; handling-induced convulsions; NMDA R1 subunit; Cyp 2E1 enzyme activity

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Differential Effects of Chronic Ethanol Treatment onN-Methyl-d-aspartate R1 Splice Variants in Fetal Cortical Neurons

Cited by 34 publications

References 36 publications

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex

Supplementing the liquid alcohol diet with chow enhances alcohol intake in C57 BL/6 mice

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