Alcohol’s effects on the brain are mediated in part through its action as a positive allosteric modulator (PAM) at GABA_A receptors (GABA_ARs), but the molecular mechanisms that connect GABA_ARs 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 GABA_AR subunits, localizes to inhibitory synapses, promotes GABA_AR surface expression, and slows receptor deactivation. TMEM132B was also required for alcohol to act as a GABA_AR 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)

酒精对大脑的影响部分是通过它作为 GABA_A 受体 （GABA_ARs） 的正变构调节剂 （PAM） 的作用来介导的，但将 GABA_ARs 与酒精相关行为联系起来的分子机制仍不清楚。为了解决这个问题，Wang 等人首先使用蛋白质组学方法检查酒精使用障碍 （AUD） 患者和对照供体个体的海马样本中质膜蛋白水平的不同水平。该筛查发现 AUD 个体的 TMEM132B 水平降低，这是一种功能未知的跨膜蛋白。作者继续证明，TMEM132B 与几个 GABA_AR 亚基结合，定位于抑制性突触，促进 GABA_AR 表面表达，并减慢受体失活。酒精也需要TMEM132B才能充当 GABA_AR PAM。最后，Tmem132b 敲除小鼠表现出酒精的抗焦虑样和镇静催眠作用降低，酗酒样饮酒增加。这些发现阐明了抑制性神经传递的基本生物学和可能构成 AUD 的机制。

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