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Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons

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 alcoh...

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Autores principales: Popova, Dina, Gameiro-Ros, Isabel, Youssef, Mark M., Zalamea, Petronio, Morris, Ayeshia D., Prytkova, Iya, Jadali, Azadeh, Kwan, Kelvin Y., Kamarajan, Chella, Salvatore, Jessica E., Xuei, Xiaoling, Chorlian, David B., Porjesz, Bernice, Kuperman, Samuel, Dick, Danielle M., Goate, Alison, Edenberg, Howard J., Tischfield, Jay A., Pang, Zhiping P., Slesinger, Paul A., Hart, Ronald P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9542475/
https://www.ncbi.nlm.nih.gov/pubmed/36207584
http://dx.doi.org/10.1038/s41380-022-01818-x
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author Popova, Dina
Gameiro-Ros, Isabel
Youssef, Mark M.
Zalamea, Petronio
Morris, Ayeshia D.
Prytkova, Iya
Jadali, Azadeh
Kwan, Kelvin Y.
Kamarajan, Chella
Salvatore, Jessica E.
Xuei, Xiaoling
Chorlian, David B.
Porjesz, Bernice
Kuperman, Samuel
Dick, Danielle M.
Goate, Alison
Edenberg, Howard J.
Tischfield, Jay A.
Pang, Zhiping P.
Slesinger, Paul A.
Hart, Ronald P.
author_facet Popova, Dina
Gameiro-Ros, Isabel
Youssef, Mark M.
Zalamea, Petronio
Morris, Ayeshia D.
Prytkova, Iya
Jadali, Azadeh
Kwan, Kelvin Y.
Kamarajan, Chella
Salvatore, Jessica E.
Xuei, Xiaoling
Chorlian, David B.
Porjesz, Bernice
Kuperman, Samuel
Dick, Danielle M.
Goate, Alison
Edenberg, Howard J.
Tischfield, Jay A.
Pang, Zhiping P.
Slesinger, Paul A.
Hart, Ronald P.
author_sort Popova, Dina
collection PubMed
description 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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spelling pubmed-95424752022-10-11 Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons Popova, Dina Gameiro-Ros, Isabel Youssef, Mark M. Zalamea, Petronio Morris, Ayeshia D. Prytkova, Iya Jadali, Azadeh Kwan, Kelvin Y. Kamarajan, Chella Salvatore, Jessica E. Xuei, Xiaoling Chorlian, David B. Porjesz, Bernice Kuperman, Samuel Dick, Danielle M. Goate, Alison Edenberg, Howard J. Tischfield, Jay A. Pang, Zhiping P. Slesinger, Paul A. Hart, Ronald P. Mol Psychiatry Article 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. Nature Publishing Group UK 2022-10-07 2023 /pmc/articles/PMC9542475/ /pubmed/36207584 http://dx.doi.org/10.1038/s41380-022-01818-x Text en © The Author(s), under exclusive licence to Springer Nature Limited 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Article
Popova, Dina
Gameiro-Ros, Isabel
Youssef, Mark M.
Zalamea, Petronio
Morris, Ayeshia D.
Prytkova, Iya
Jadali, Azadeh
Kwan, Kelvin Y.
Kamarajan, Chella
Salvatore, Jessica E.
Xuei, Xiaoling
Chorlian, David B.
Porjesz, Bernice
Kuperman, Samuel
Dick, Danielle M.
Goate, Alison
Edenberg, Howard J.
Tischfield, Jay A.
Pang, Zhiping P.
Slesinger, Paul A.
Hart, Ronald P.
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
title Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
title_full Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
title_fullStr Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
title_full_unstemmed Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
title_short Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
title_sort alcohol reverses the effects of kcnj6 (girk2) noncoding variants on excitability of human glutamatergic neurons
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9542475/
https://www.ncbi.nlm.nih.gov/pubmed/36207584
http://dx.doi.org/10.1038/s41380-022-01818-x
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