Ramanathan R, Wilkemeyer M F, Mittal B, Perides G, Charness M E
Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
J Cell Biol. 1996 Apr;133(2):381-90. doi: 10.1083/jcb.133.2.381.
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. L1-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited L1-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. L1-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 L1-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of L1-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 L1-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders.
在胎儿酒精综合征（FAS）以及细胞黏附分子L1基因发生突变的儿童中，均观察到智力发育迟缓、脑积水和胼胝体发育不全的情况。我们研究了乙醇对转染了人L1的小鼠成纤维细胞中细胞间黏附的影响。与野生型或载体转染的对照相比，转染L1的成纤维细胞表现出细胞间黏附增加。乙醇在转染的L细胞和NIH/3T3细胞中均能有效且完全抑制L1介导的黏附。在7 mM乙醇时观察到半数最大抑制，摄入一杯酒精饮料后血液和大脑中可达到该浓度。相比之下，乙醇并不抑制单独转染载体或转染N-CAM-140的成纤维细胞的黏附。正丙醇和正丁醇对L1介导的细胞间黏附的抑制作用随浓度增加而增强，但含5至8个碳的正醇、乙醛或乙酸盐对其完全没有抑制作用，这表明乙醇直接与L1内的一个小疏水口袋相互作用。苯丙氨酸、致畸性抗惊厥药和高浓度葡萄糖均不抑制L1介导的细胞间黏附。乙醇还能有效抑制大鼠小脑颗粒细胞与转染L1的NIH/3T3细胞单层的异型黏附，但对它们与N-CAM-140或载体转染的NIH/ST3细胞的黏附没有影响。由于L1在神经发育和学习中均起作用，乙醇对L1介导的细胞间相互作用的抑制可能导致胎儿酒精综合征和与乙醇相关的记忆障碍。
