Alcohol inhibits cell-cell adhesion mediated by human L1 [published erratum appears in J Cell Biol 1996 Jun;133(5):1139-40]

Abstract

Abstract. Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. Ll-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited Ll-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. Ll-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit Ll-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of Ll-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of Ll-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders. FETAL alcohol syndrome (FAS) 1 is one of the most common recognizable syndromes associated with mental retardation in the Western world (1). The full syndrome, characterized by growth retardation, neurological abnormalities, and facial malformations, occurs in N5% of the offspring of alcoholic women (1, 72). Neuropathological examination and neuroimaging of children with FAS have disclosed a spectrum of neurodevelopmental abnormalities, including hydrocephalus, agenesis of the corpus callosum, neuronal-glial heterotopias, cerebellar dysplasia, and microcephaly (8,27,62). Some of these lesions arise from disordered migration of neural cells, which has also been demonstrated experimentally in animal models of FAS (45,46 X-linked syndrome associated with mutations in the gene encoding L1, an immunoglobulin cell adhesion molecule (IgCAM) (4,20,28,31,66,74,83). Three overlapping syndromes, X-linked hydrocephalus, MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and X-linked complicated spastic paraplegia, were each mapped to the same region (Xq28) of the X chromosome (32,76,82). A large number of different missense mutations, short deletions, and defects of alternative splicing within the L1 gene have been identified in individuals with these X-linked disorders (83); similar mutations have never been encountered in large numbers of control subjects. A single point mutation in L1 can cause either X-linked hydro...

Antagonists of alcohol inhibition of cell adhesion

“…Cell-cell adhesion is inhibited with increasing potency by methanol, ethanol, 1-propanol, and 1-butanol (10,11). This suggests that shortchain 1-alcohols interact with a hydrophobic recognition site.…”

“…The pharmacological profile of 20 different alcohols is identical in the two cellular systems, consistent with the existence of a common molecular target. Previous data suggest that this target is L1 or an L1-associated protein (11)(12)(13).…”

“…1-Alcohol inhibition of cell-cell adhesion demonstrates an abrupt cutoff effect between 1-butanol and 1-pentanol (10,11), consistent with a direct effect on L1 or an associated protein.…”

“…We have shown that clinically relevant concentrations of ethanol inhibit cell-cell adhesion mediated by L1 in transfected fibroblasts and in the NG108-15 neuroblastoma ϫ glioma cell line (10)(11)(12)(13). In NG108-15 cells, ethanol also inhibits morphogenetic changes induced by BMP-7, a powerful inducer of L1 and neural cell adhesion molecule (N-CAM) gene expression (10).…”

“…In NG108-15 cells, ethanol also inhibits morphogenetic changes induced by BMP-7, a powerful inducer of L1 and neural cell adhesion molecule (N-CAM) gene expression (10). Because of the similarity in brain lesions in children with fetal alcohol syndrome and those with mutations in the gene for L1, we have speculated that ethanol effects on L1 could play a role in the pathophysiology of fetal alcohol syndrome (11). Interestingly, ethanol potently inhibits L1-mediated neurite extension in cerebellar granule cells (14).…”