Cell surface expression of NR1 splice variants and NR2 subunits is modified by prenatal ethanol exposure

Honse, Yumiko; Nixon, Kimberly; Browning, Michael; Leslie, Steven W.

doi:10.1016/s0306-4522(03)00603-1

Cited by 23 publications

(21 citation statements)

References 37 publications

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“…No change in the mRNA for C-terminal NR1 splice variants was found following treatment of adult rats to ethanol in one study (Hardy et al, 1999), while another (Darstein et al, 2000) found slight increases in NR1-1 and NR1-3 variants and decreases in NR1-2 and NR1-4 forms. In a separate study, prenatal ethanol exposure did not change the cell surface expression of exon-5-containing NR1 subunit protein (NR1b variants) as measured in 21-day-old rats (Honse et al, 2003). However, these animals did show a reduction in protein levels of NR1-4 splice subunits (C2 0 containing) in samples immunoprecipitated with an antibody to PSD-95 to isolate postsynaptic membranes (Honse et al, 2003).…”

Section: Discussionmentioning

confidence: 89%

“…In a separate study, prenatal ethanol exposure did not change the cell surface expression of exon-5-containing NR1 subunit protein (NR1b variants) as measured in 21-day-old rats (Honse et al, 2003). However, these animals did show a reduction in protein levels of NR1-4 splice subunits (C2 0 containing) in samples immunoprecipitated with an antibody to PSD-95 to isolate postsynaptic membranes (Honse et al, 2003). The results of these studies generally support a role for NR1 splice variants in the adaptation to chronic ethanol exposure, although it is clear that additional studies are needed to systematically categorize the effects of chronic ethanol exposure on NR1 splice variants in model systems that show reproducible effects on NMDA receptor function.…”

Section: Discussionmentioning

confidence: 91%

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Effects of 8 Different NR1 Splice Variants on the Ethanol Inhibition of Recombinant NMDA Receptors

Jin¹,

Woodward²

2006

Alcoholism Clin & Exp Res

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 91%

Effects of 8 Different NR1 Splice Variants on the Ethanol Inhibition of Recombinant NMDA Receptors

Jin¹,

Woodward²

2006

Alcoholism Clin & Exp Res

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“…The NR1 subunits comprise a number of splice variants, and the NR1 slice variants determine the localization and trafficking of the subunit (11,14,38,39). The C0 region within the NR1 subunit was identified as an important region for regulating NMDAR sensitivity to ethanol (40,41), and prenatal exposure of cerebral cortical neurons to ethanol resulted in the reduction in the levels of the C2Ј variant (42). Thus, it would be of interest to test whether acute ethanol treatment may be involved in the trafficking or levels of certain NR1 splice variants.…”

Section: Discussionmentioning

confidence: 99%

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Suvarna

Borgland

Wang

et al. 2005

Journal of Biological Chemistry

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The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B-to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity. NMDARs1 are major mediators of processes such as synaptic plasticity and learning and memory (1) and of pathological states such as schizophrenia, seizures, pain, drug and alcohol addiction (2-5), and alcohol intoxication (6).NMDARs are heteromeric ligand-gated ion channels composed of an obligatory NR1 subunit and regulatory NR2A-D and NR3 subunits (2). The NMDAR subunits can undergo lateral movement between synaptic and extrasynaptic sites, as well as internalization from, or forward trafficking to, the plasma membrane (7,8). For example, prolonged inhibition of NMDAR activity results in the redistribution of the subunits from extrasynaptic to synaptic sites (9). Synaptic activity and long-term potentiation increase the forward trafficking of NMDAR subunits (10, 11), and glycine has been reported to prime the NMDAR subunits for internalization (12).NMDAR function can be regulated by changes in the phosphorylation state of the subunits via the activation of kinases or phosphatases (13). Protein phosphorylation and dephosphorylation also control the movement of NMDAR subunits to and from the plasma membrane. For example, activation of protein kinase C and cAMP-dependent protein kinase A, and the consequent phosphorylation of the NR1 subunit, increases forward trafficking of the receptor (14). Fyn kinase-mediated tyrosine phosphorylation of the NMDAR plays a role in the dopamine D1 receptor-mediated redistribution of NMDAR subunits from intracellular to postsynaptic compartments (15). Conversely, tyrosine dephosphorylation of the NR2A subunits leads to the internalization of the subunits, resulting in the rundown of channel activity (16). In addition, we recently found that H-Ras-mediated inhibition of Src kinase activity prevents the phosphorylation and membrane retention of NR2A subunits (17).We, and others, reported that the activity of the NMDAR in the presence of ethanol is modulated via changes in the phosphorylation state of the subunits (18 -20). NMDARs have been implicated in mediating ethanol-associated phenotypes such as tolerance, dependence, withdrawal, craving and relapse, ...

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“…There is compelling evidence that alcohol and alcohol dependence affect alternative splicing mechanisms of various genes (Sasabe and Ishiura, 2010). For example, alcohol affects pre-mRNA alternative splicing at DRD2 which encodes the dopamine type 2 receptor (Wernicke et al, 2010), NMDA receptor NR1 subunit encoded by GRIN1 that can produce as many as eight spliced variants (Hardy et al, 1999; Honse et al, 2003; Kumari, 2001), and BK channel alpha1 subunit (Pietrzykowski et al, 2008). In addition, altered GABA-B receptor subunit 1 splicing is observed in human alcoholic post-mortem brain (Lee et al, 2014).…”

Section: Genome-wide Association Studies Of Alcohol Dependencementioning

confidence: 99%

Genetic studies of alcohol dependence in the context of the addiction cycle

et al. 2017

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Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50–60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled “Alcoholism”.

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Cell surface expression of NR1 splice variants and NR2 subunits is modified by prenatal ethanol exposure

Cited by 23 publications

References 37 publications

Effects of 8 Different NR1 Splice Variants on the Ethanol Inhibition of Recombinant NMDA Receptors

Effects of 8 Different NR1 Splice Variants on the Ethanol Inhibition of Recombinant NMDA Receptors

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Genetic studies of alcohol dependence in the context of the addiction cycle

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