Alcohol dependence: molecular and behavioral evidence

• Structural, computer modeling, and mutagenesis studies reveal direct sites for alcohol on ligand-gated ion channels (LGICs).
• Alcohol alters ion channel function indirectly via receptor phosphorylation and trafficking.
• Mutant mice and genetic association studies demonstrate the role of LGICs in alcohol dependence.
• Combining structural, functional, behavioral, and genomic approaches is crucial for identifying sites of alcohol action.

Alcohol dependence is a complex condition with clear genetic factors. Some of the leading candidate genes code for subunits of the inhibitory GABAA and glycine receptors. These and related ion channels are also targets for the acute actions of alcohol, and there is considerable progress in understanding interactions of alcohol with these proteins at the molecular and even atomic levels. X-ray structures of open and closed states of ion channels combined with structural modeling and site-directed mutagenesis have elucidated direct actions of alcohol. Alcohol also alters channel function by translational and post-translational mechanisms, including phosphorylation and protein trafficking. Construction of mutant mice with either deletion of key proteins or introduction of alcohol-resistant channels has further linked specific proteins with discrete behavioral effects of alcohol. A combination of approaches, including genome wide association studies in humans, continues to advance the molecular basis of alcohol action on receptor structure and function.