An alcohol binding site on the neural cell adhesion molecule L1

Arevalo, Enrique; Shanmugasundararaj, Sivananthaperumal; Wilkemeyer, Michael F.; Dou, Xiaowei; Chen, Suzhen; Charness, Michael E.; Miller, Keith W.

doi:10.1073/pnas.0707815105

Cited by 62 publications

(64 citation statements)

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“…It appears likely that presentation of purified L1 outside of a cellular context disrupts the specific conformation of the alcohol binding pocket that is required for ethanol inhibition of L1 adhesion. This observation is consistent with our recent report that an alcohol binding pocket at the Ig1-Ig4 interface of L1 is susceptible to minor structural modifications (31,44).…”

Section: Discussionsupporting

confidence: 82%

“…(A) The L1 extracellular domain (L1-ECD) folds into a horseshoe structure that favors L1 adhesion. An alcohol binding pocket has been identified at the interface between Ig1 and Ig4, and ethanol appears to inhibit L1 adhesion by disrupting this horseshoe structure (31,44). Phosphorylation of S1248 by ERK2 is proposed to induce a conformational change in the L1-ECD (inside-out signaling) that favors ethanol binding within this pocket.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse L1-ECD-Fc (mL1-Ig1-6-Fn3-1-5-Fc) was prepared as described (44,49) and digested with AcTEV Protease (Invitrogen) to remove Fc. Polybead Carboxylate Blue Dyed 1-μm microspheres (Polysciences Inc.) were coated with mL1-ECD protein at a ratio of 8 × 10 9 beads per μg of L1 protein or 8 × 10 9 beads per 3 μg of BSA using the Glutaraldehyde Kit (Polysciences Inc.), according to the manual.…”

Section: Methodsmentioning

confidence: 99%

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Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Dou

Wilkemeyer

Menkari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity. P renatal alcohol exposure causes fetal alcohol spectrum disorders (FASD) in up to 2-5% of school-age children and is the leading preventable cause of mental retardation in the Western world (1, 2). The prevalence and presentation of FASD are influenced by the quantity, frequency, and timing of drinking and are modified by a variety of environmental, nutritional, epigenetic, and genetic factors (3-7). The observation that there is greater concordance for fetal alcohol syndrome (FAS) in monozygotic twins than in dizygotic twins suggests that there are susceptibility genes for FASD (8); however, their identification remains elusive. The identification of molecular pathways that regulate sensitivity to ethanol teratogenesis would be helpful in the search for FASD susceptibility genes.One potentially important target of ethanol in the pathogenesis of FASD is the developmentally critical immunoglobulin neural cell adhesion molecule, L1. The homophilic binding of L1 molecules on adjacent cells mediates neuronal migration, axon guidance, and axon fasciculation (9)-developmental events that are disrupted in FASD (10-12). Mutations in the human L1 gene cause brain lesions and neurological abnormalities. Some of these mutations also disrupt L1 homophilic binding (13-16). We noted that brain lesions in children with FASD resemble those of child...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Dou

Wilkemeyer

Menkari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Prejuízo da memória, atenção e aprendizado são os efeitos mais comuns da SAF, que é também a causa de retardo mental passível de prevenção mais comum 13 . O quociente de inteligência (QI) médio de crianças com SAF é estimado ser abaixo de 70, porém muitas delas não apresentam retardo mental e o QI se apresenta numa escala de 20 a 120.…”

Section: Danos Neuroteratogênicosunclassified

Exposição pré-natal ao etanol: toxicidade, biomarcadores e métodos de detecção

Cassini¹,

Linden²

2011

Rev. psiquiatr. clín.

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ResumoContexto: A exposição pré-natal ao etanol pode produzir diversos efeitos adversos no desenvolvimento fetal denominados doença espectral do alcoolismo fetal (DEAF). A detecção precoce de exposição ao etanol permite que medidas preventivas sejam tomadas para minimizar os efeitos adversos da exposição. Objetivos: O presente trabalho teve como objetivo revisar os principais efeitos tóxicos do etanol no neonato e os biomarcadores de exposição ao álcool. Métodos: Foi realizada uma pesquisa bibliográfica na base de dados PubMed utilizando os descritores "effects maternal ethanol exposure" e "biomarkers ethanol prenatal exposure", além de referências cruzadas dos artigos selecionados. Resultados: Diversos efeitos adversos no desenvolvimento fetal têm sido descritos, especialmente os prejuízos no sistema nervoso central. Os biomarcadores de exposição mais citados na literatura são os etil ésteres de ácidos graxos (EEAG), etil glicuronídeo (EtG) e etil sulfato (EtS) utilizando mecônio e cabelo como matriz biológica. Conclusão: A detecção precoce de exposição ao álcool na vida intrauterina pode ser realizada e é um instrumento para prevenir efeitos secundários, porque possibilita a intervenção farmacológica e educacional na criança com DEAF. Cassini C, Linden R / Rev Psiq Clín. 2011;38(3):116-21Palavras-chave: Exposição pré-natal ao etanol, doença espectral do alcoolismo fetal, biomarcadores de exposição ao etanol. AbstractBackground: Prenatal exposure to ethanol can produce a complex set of effects on fetal development, which is denominated fetal alcohol spectrum disorder (FASD). Early detection of ethanol exposure can allow the prevention of some relevant adverse effects associated to FASD. Objectives: The aim of this work was to review the main toxic effects of ethanol on the neonate and the available biomarkers of prenatal alcohol exposure. Methods: A bibliographic search was performed in PubMed employing the terms "effects maternal ethanol exposure" and "biomarkers ethanol prenatal exposure" and cross references. Results: Many adverse effects on fetal development were described, especially deficits in the central nervous system. The biomarkers of ethanol exposure more widely described were fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG) and ethyl sulphate (EtS), being meconium and hair the most common biological matrices for laboratorial evaluation. Discussion: The early detection of alcohol exposure in intra-uterine life is useful to prevent the secondary effects of FASD through pharmacologic and educational intervention in affected children.

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“…Ethanol alters growth cone dynamics and L1 function can restore proper response to guidance cues (19). Using photoactivatable forms of butanol and octanol, an ethanol-binding pocket was discovered between the interface of the first and forth Ig domains of L1 (20), suggesting that ethanol may alter the conformation of the extracellular domain.…”

mentioning

confidence: 99%