ArticleMolecular psychiatry2023
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.
Article in Molecular psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
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- Heavy adolescent drinking makes the adult brain more vulnerable to ethanol by permanently altering the age-dependent interplay between alcohol, GIRK channels and activin.Molecular psychiatry · 2026Article
- Whole Genome Sequencing of Pedigrees With High Density of Substance Use and Psychiatric Disorders: A Meeting Report.Genes, brain, and behavior · 2025Article
- Chronic ethanol exposure in mice evokes pre- and postsynaptic deficits in GABAergic transmission in ventral tegmental area GABA neurons.British journal of pharmacology · 2025Article
- Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model.Science advances · 2024Article
- Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- A critical review of ethanol effects on neuronal firing: A metabolic perspective.Alcohol, clinical & experimental research · 2024Review
- Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels.Frontiers in physiology · 2024Review
- The collaborative study on the genetics of alcoholism: Brain function.Genes, brain, and behavior · 2023Review
- The Collaborative Study on the Genetics of Alcoholism: Overview.Genes, brain, and behavior · 2023Review
- 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics.Genes, brain, and behavior · 2023Review
- The collaborative study on the genetics of alcoholism: Genetics.Genes, brain, and behavior · 2023Review
- The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
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Authors and funding
21 authors at 5 institutions in 1 country.
Funding
Abstract
Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants ("Affected: AF") and four control subjects without variants ("Unaffected: UN"). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single-cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.
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