Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.
- Authors
- Prytkova, Iya; Liu, Yiyuan; Fernando, Michael; Gameiro-Ros, Isabel; Popova, Dina; Kamarajan, Chella; Xuei, Xiaoling; Chorlian, David B; Edenberg, Howard J; Tischfield, Jay A; Porjesz, Bernice; Pang, Zhiping P; Hart, Ronald P; Goate, Alison; Slesinger, Paul A
- Year
- 2024
- Journal
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- PMID
- 38350999
- DOI
- 10.1523/JNEUROSCI.0918-23.2024
- PMCID
- PMC11026340
- Preprint
- Upregulated GIRK2 counteracts ethanol-induced changes in excitability & respiration in human neurons. (2024)
Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the gene. encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating 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.
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| A critical review of ethanol effects on neuronal firing: A metabolic perspective. | Popova D et al. | — | 2024 | → |
| Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels. | Nguyen H et al. | — | 2024 | → |
| Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor. | Colombo S et al. | — | 2023 | → |