The TMEM132B-GABAA receptor complex controls alcohol actions in the brain

Alcohol is the most consumed and abused psychoactive drug globally, but the molecular mechanisms driving alcohol action and its associated behaviors in the brain remain enigmatic. Here, we have discovered a transmembrane protein TMEM132B that is a GABAA receptor (GABAAR) auxiliary subunit. Functionally, TMEM132B promotes GABAAR expression at the cell surface, slows receptor deactivation, and enhances the allosteric effects of alcohol on the receptor. In TMEM132B knockout (KO) mice or TMEM132B I499A knockin (KI) mice in which the TMEM132B-GABAAR interaction is specifically abolished, GABAergic transmission is decreased and alcohol-induced potentiation of GABAAR-mediated currents is diminished in hippocampal neurons. Behaviorally, the anxiolytic and sedative/hypnotic effects of alcohol are markedly reduced, and compulsive, binge-like alcohol consumption is significantly increased. Taken together, these data reveal a GABAAR auxiliary subunit, identify the TMEM132B-GABAAR complex as a major alcohol target in the brain, and provide mechanistic insights into alcohol-related behaviors. [Display omitted] •Single-pass transmembrane protein TMEM132B is a GABAAR auxiliary subunit•TMEM132B promotes GABAAR expression at the cell surface and slows receptor deactivation•TMEM132B enhances the allosteric effects of alcohol on various GABAARs•Genetic inactivation of TMEM132B in mice alters alcohol-related behaviors Identification of TMEM132B as a GABAAR auxiliary subunit that modulates alcohol action in the brain at both the molecular and behavioral levels.