HMS researchers have discovered a novel alcohol binding site on the neural cell adhesion molecule L1. The study, an early step to finding drugs to reduce ethanol toxicity on the nervous system, appears in the Jan. 8 Proceedings of the National Academy of Sciences.
L1 molecules on one nerve cell adhere to L1s on other nerve cells and are critical for normal brain development. Children with L1 gene mutations have mental retardation, thinning or absence of the corpus callosum, hydrocephalus, and malformation of the cerebellum. Michael Charness, co–senior author and an HMS professor of neurology at the VA Boston Healthcare System, began studying L1 when he noticed that children with fetal alcohol spectrum disorders (FASD) have brain lesions similar to those of children with L1 mutations.
Charness and colleagues have reported that alcohols with fewer than four carbons inhibit L1 adhesion, while certain alcohols containing five or more carbons block the action of small alcohols on L1 and prevent ethanol teratogenesis in mice.
Initially, Charness could not easily determine if L1 had an alcohol binding site because of alcohol’s low affinity for its targets. “Alcohol comes off the receptor almost instantly,” he said. “That’s why you need a high concentration of alcohol in your blood to have an effect.”
He joined forces with the lab of co–senior author Keith Miller, the Mallinckrodt professor of pharmacology in the Department of Anesthesia at Massachusetts General Hospital. The researchers used a photolabeling technique to pinpoint the binding site and identified the critical amino acids via mass spectrometry. The site was located where two domains of the L1 molecule interact, stabilizing the molecule’s horseshoe-shaped structure.
The researchers hypothesize that ethanol breaks the hydrogen bond holding two particular amino acids together. Once the bond is broken, the L1 molecule is more likely to unfold and lose its adhesive properties, the authors said.
Charness and Miller hope to crystallize the L1 molecule to obtain a three-dimensional image of the binding site so they can begin searching for drugs that could protect L1 from ethanol. “The ultimate goal of the research is to develop medications that will decrease alcohol toxicity in the nervous system,” said Charness. “If a woman who is eight weeks pregnant comes into an emergency room with severe alcohol intoxication, that might be an opportunity for using a drug that blocks some of the effects of alcohol on development.”
