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

Affiliations

• Department of Biology, Johns Hopkins University, Baltimore, MD, USA
• Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
• Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
• Department of Chemistry, University of Konstanz, Konstanz, Germany
• Department of Biology, University of Konstanz, Konstanz, Germany
• Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
• Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

PMID:  39357522  DOI: 10.1016/j.cell.2024.09.006

Abstract

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.

酒精是全球范围内最常被消费和滥用的精神活性药物，但其在大脑中作用及相关行为的分子机制仍然不明。本文中，我们发现了一种跨膜蛋白TMEM132B，它是GABAA受体（GABAAR）的辅助亚基。在功能上，TMEM132B促进了GABAAR在细胞表面的表达，延缓了受体去活化，并增强了酒精对该受体的变构效应。在TMEM132B敲除（KO）小鼠或TMEM132B I499A敲入（KI）小鼠中，TMEM132B与GABAAR的相互作用被特异性消除，海马神经元中的GABA能传递减弱，且酒精引起的GABAAR介导电流的增强效应减少。在行为上，酒精的抗焦虑及镇静/催眠作用显著减弱，而强迫性、暴饮暴食式的酒精摄入明显增加。综上所述，这些数据揭示了一种GABAAR辅助亚基，确定了TMEM132B-GABAAR复合物是大脑中的主要酒精靶点，并提供了酒精相关行为的机制性见解。