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Research ArticleArticle

GABAA Receptors Expressed in Oligodendrocytes Cultured from the Neonatal Rat Contain α3 and γ1 Subunits and Present Differential Functional and Pharmacological Properties

Rainald Pablo Ordaz, Edith Garay, Agenor Limon, Alberto Pérez-Samartín, María Victoria Sánchez-Gómez, Leticia Robles-Martínez, Abraham Cisneros-Mejorado, Carlos Matute and Rogelio O. Arellano
Molecular Pharmacology February 2021, 99 (2) 133-146; DOI: https://doi.org/10.1124/molpharm.120.000091
Rainald Pablo Ordaz
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Edith Garay
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Agenor Limon
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Alberto Pérez-Samartín
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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María Victoria Sánchez-Gómez
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Leticia Robles-Martínez
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Abraham Cisneros-Mejorado
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Carlos Matute
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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  • For correspondence: carlos.matute@ehu.eus
Rogelio O. Arellano
Instituto de Neurobiología, Laboratorio de Neurofisiología Celular, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México (R.P.O., E.G., L.R.-M., A.C.-M., R.O.A.); Mitchell Center for Neurodegenerative Diseases, Department of Neurology, School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas (A.L.); and Achucarro Basque Center for Neuroscience, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain (A.P.-S., M.V.S.-G., C.M.)
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Abstract

Oligodendrocytes (OLs) express functional GABAA receptors (GABAARs) that are activated by GABA released at synaptic contacts with axons or by ambient GABA in extrasynaptic domains. In both instances, the receptors’ molecular identity has not been fully defined. Furthermore, data on their structural diversity in different brain regions and information on age-dependent changes in their molecular composition are scant. This lack of knowledge has delayed access to a better understanding of the role of GABAergic signaling between neurons and OLs. Here, we used functional, and pharmacological analyses, as well as gene and protein expression of GABAAR subunits, to explore the subunit combination that could explain the receptor functional profile expressed in OLs from the neonate rat. We found that GABAAR composed of α3β2γ1 subunits mimicked the characteristics of the endogenous receptor when expressed heterologously in Xenopus laevis oocytes. Either α3 or γ1 subunit silencing by small interfering RNA transfection changed the GABA-response characteristics in oligodendrocyte precursor cells, indicating their participation in the endogenous receptor conformation. Thus, α3 subunit silencing shifted the mean EC50 for GABA from 75.1 to 46.6 µM, whereas γ1 silencing reduced the current amplitude response by 55%. We also observed that β-carbolines differentially enhance GABA responses in oligodendroglia as compared with those in neurons. These results contribute to defining the molecular and pharmacological properties of GABAARs in OLs. Additionally, the identification of β-carbolines as selective enhancers of GABAARs in OLs may help to study the role of GABAergic signaling during myelination.

Significance Statement GABAergic signaling through GABAA receptors (GABAARs) expressed in the oligodendroglial lineage contributes to the myelination control. Determining the molecular identity and the pharmacology of these receptors is essential to define their specific roles in myelination. Using GABAAR subunit expression and silencing, we identified that the GABAAR subunit combination α3β2γ1 conforms the bulk of GABAARs in oligodendrocytes from rat neonates. Furthermore, we found that these receptors have differential pharmacological properties that allow specific positive modulation by β-carbolines.

Footnotes

    • Received June 12, 2020.
    • Accepted November 5, 2020.
  • This study was supported by grants from CONACYT-México [No. 252121] and PAPIIT UNAM-México [No. IN203519] to R.O.A.’s laboratory; National Institutes of Health National Institute of Aging [Grant R21-AG053740] and National Institute of Mental Health [Grant R21-MH113177] and the Amon G. Carter Foundation to A.L.; and CIBERNED [CB06/05/0076] and the Ministry of Economy and Competitiveness, Government of Spain [SAF2016-75292-R] and Basque Government [IT1203-19] to C.M.

  • Some information reported herein was presented during a poster session by Rainald Pablo Ordaz, Edith Garay, Carlos Matute, and Rogelio O. Arellano at the “XIV European Meeting on Glial Cells in Health and Disease, GLIA 2019” on 2019 July 10–13.

  • https://doi.org/10.1124/molpharm.120.000091.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
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Research ArticleArticle

GABAAR Molecular Identity in Oligodendrocytes

Rainald Pablo Ordaz, Edith Garay, Agenor Limon, Alberto Pérez-Samartín, María Victoria Sánchez-Gómez, Leticia Robles-Martínez, Abraham Cisneros-Mejorado, Carlos Matute and Rogelio O. Arellano
Molecular Pharmacology February 1, 2021, 99 (2) 133-146; DOI: https://doi.org/10.1124/molpharm.120.000091

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Research ArticleArticle

GABAAR Molecular Identity in Oligodendrocytes

Rainald Pablo Ordaz, Edith Garay, Agenor Limon, Alberto Pérez-Samartín, María Victoria Sánchez-Gómez, Leticia Robles-Martínez, Abraham Cisneros-Mejorado, Carlos Matute and Rogelio O. Arellano
Molecular Pharmacology February 1, 2021, 99 (2) 133-146; DOI: https://doi.org/10.1124/molpharm.120.000091
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