Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.
Iya PrytkovaYiyuan LiuMichael FernandoIsabel Gameiro-RosDina PopovaChella KamarajanXiaoling XueiDavid B ChorlianHoward J EdenbergJay A TischfieldBernice PorjeszZhiping P PangRonald P HartAlison GoatePaul A SlesingerPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2024)
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.
Keyphrases
- induced pluripotent stem cells
- endothelial cells
- alcohol use disorder
- spinal cord
- single cell
- pluripotent stem cells
- oxidative stress
- high glucose
- transcranial direct current stimulation
- high resolution
- high throughput
- gene expression
- diabetic rats
- genome wide
- machine learning
- copy number
- rna seq
- mass spectrometry
- photodynamic therapy
- deep learning
- spinal cord injury
- brain injury
- cerebral ischemia
- blood brain barrier