biostudies-literaturePrytkova INational Institute of Alcohol Abuse and AlcoholismNIAAA NIH HHSNIH HHSe0918232024https://www.ebi.ac.uk/biostudies/studies/S-EPMC11026340biostudies-literatureUnknown44(16)Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the <i>KCNJ6</i> gene. <i>KCNJ6</i> encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating <i>KCNJ6</i> 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, The Journal of neuroscience : the official journal of the Society for NeuroscienceUpregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.PMC11026340S10 OD030463U10 AA008401S10 OD026880F31 AA027949F31AA027949-01U10AA008401Hart RPPrytkova IEdenberg HJPorjesz BTischfield JAFernando MGameiro-Ros IPopova DLiu YSlesinger PAXuei XChorlian DBKamarajan CPang ZPGoate AfalseUpregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the <i>KCNJ6</i> gene. <i>KCNJ6</i> encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating <i>KCNJ6</i> 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, 2024-01-01T00:00:00Z2024 Apr2026-07-15T05:10:20.628Z2026-06-30T03:08:51.932ZS-EPMC110263403835099910.1523/JNEUROSCI.0918-23.202410.1523/jneurosci.0918-23.2024