Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the KCNJ6 gene. KCNJ6 encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating KCNJ6 using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multielectrode arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7–21 d of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-induced changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons.

酒精使用障碍 (AUD) 脑电图内表型的全基因组关联研究 (GWAS) 发现了KCNJ6基因内的非编码多态性。KCNJ6编码 GIRK2，GIRK2 是 G 蛋白偶联内向整流钾通道的一个亚基，可调节神经元兴奋性。我们使用同基因方法研究了来自诱导多能干细胞（男性和女性供体）的人谷氨酸能神经元上调KCNJ6的效果。使用多电极阵列、群体钙成像、单细胞膜片钳电生理学和线粒体应激测试，我们发现升高的 GIRK2 与乙醇暴露 7-21 天协同作用，抑制神经元活动，抵消乙醇诱导的谷氨酸增加反应，并促进内在兴奋性的增加。此外，升高的 GIRK2 可以阻止乙醇诱导的基础和活性依赖性线粒体呼吸的变化。这些数据支持 GIRK2 在减轻乙醇影响方面的作用，以及以前未知的与人谷氨酸能神经元线粒体功能的联系。