Alcohol’s effects on the brain are mediated in part through its action as a positive allosteric modulator (PAM) at GABAA receptors (GABAARs), but the molecular mechanisms that connect GABAARs and alcohol-related behaviors remain unclear. To address this question, Wang et al. began by using a proteomic approach to examine differential levels of plasma membrane proteins in hippocampal samples from individuals with alcohol use disorder (AUD) and control donors. This screen identified reduced levels of TMEM132B, a transmembrane protein of unknown function, in individuals with AUD. The authors went on to demonstrate that TMEM132B binds to several GABAAR subunits, localizes to inhibitory synapses, promotes GABAAR surface expression, and slows receptor deactivation. TMEM132B was also required for alcohol to act as a GABAAR PAM. Finally, Tmem132b knockout mice exhibited reduced anxiolytic-like and sedative–hypnotic effects of alcohol and increased binge-like drinking. These findings illuminate both the basic biology of inhibitory neurotransmission and mechanisms that might underlie AUD.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.09.006 (2024)