Alcohol dependence: molecular and behavioral evidence

Abstract

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.

Keywords: GABA(A); GLIC; LGICs; NMDA; PKC; behavior; chronic alcohol consumption; crystal structures; ethanol; gene expression; glycine; knockin mice; knockout; trafficking.

Figure 1. X-ray structures of wild-type and ethanol-sensitized GLIC

(a) Wild-type GLIC (PDB ID 4HFI), colored by residue B-factor according to scale at bottom. For clarity, two proximal subunits are hidden, revealing three distal subunits surrounding channel pore. Lower panel shows inter-subunit transmembrane cavity (light grey surface) formed by the extracellular portions of M1–M2 from one subunit and M2–M3 from the neighboring subunit, and occluded on one end by the F140 side chain (dark grey spheres). (b) Ethanol-sensitized GLIC variant (F140A) (PDB ID 4HFB), depicted as in panel (a). Lower panel shows expanded inter-subunit cavity containing resolved water (red sphere). (c) GLIC F140A mutant co-crystallized with ethanol (PDB ID4HFE), depicted as in panel (a). Lower panel shows inter-subunit cavity containing ethanol (orange and red spheres). Figure and legend are from Saguet et al., 2013 [19].