Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors

Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability...

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Autores principales:	Braulio Muñoz, Trinidad Mariqueo, Pablo Murath, Christian Peters, Gonzalo E. Yevenes, Gustavo Moraga-Cid, Robert W. Peoples, Luis G. Aguayo
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	receptor pharmacology glycine receptor ethanol allosteric modulation G-protein Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/a1e12b7b340445f3965359c8b8f2cef4
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spelling	oai:doaj.org-article:a1e12b7b340445f3965359c8b8f2cef42021-11-18T09:41:28ZModulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors1662-509910.3389/fnmol.2021.763868https://doaj.org/article/a1e12b7b340445f3965359c8b8f2cef42021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnmol.2021.763868/fullhttps://doaj.org/toc/1662-5099Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication. We evaluated the role of β GlyR subunits and of two basic amino acid residues, K389 and R390, located in the large intracellular loop (IL) of the α2 GlyR subunit, which are important for binding and functional modulation by Gβγ, the dimer of the trimeric G protein conformation, using HEK-293 transfected cells combined with patch clamp electrophysiology. We demonstrate a new modulatory role of the β subunit on ethanol sensitivity of α2 subunits. Specifically, we found a differential allosteric modulation in homomeric α2 GlyRs compared with the α2β heteromeric conformation. Indeed, while α2 was insensitive, α2β GlyRs were substantially potentiated by ethanol, GTP-γ-S, propofol, Zn2+ and trichloroethanol. Furthermore, a Gβγ scavenger (ct-GRK2) selectively attenuated the effects of ethanol on recombinant α2β GlyRs. Mutations in an α2 GlyR co-expressed with the β subunit (α2AAβ) specifically blocked ethanol sensitivity, but not propofol potentiation. These results show a selective mechanism for low ethanol concentration effects on homomeric and heteromeric conformations of α2 GlyRs and provide a new mechanism for ethanol pharmacology, which is relevant to upper brain regions where α2 GlyRs are abundantly expressed.Braulio MuñozTrinidad MariqueoPablo MurathChristian PetersGonzalo E. YevenesGustavo Moraga-CidRobert W. PeoplesLuis G. AguayoFrontiers Media S.A.articlereceptor pharmacologyglycine receptorethanolallosteric modulationG-proteinNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Molecular Neuroscience, Vol 14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	receptor pharmacology glycine receptor ethanol allosteric modulation G-protein Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	receptor pharmacology glycine receptor ethanol allosteric modulation G-protein Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Braulio Muñoz Trinidad Mariqueo Pablo Murath Christian Peters Gonzalo E. Yevenes Gustavo Moraga-Cid Robert W. Peoples Luis G. Aguayo Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
description	Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication. We evaluated the role of β GlyR subunits and of two basic amino acid residues, K389 and R390, located in the large intracellular loop (IL) of the α2 GlyR subunit, which are important for binding and functional modulation by Gβγ, the dimer of the trimeric G protein conformation, using HEK-293 transfected cells combined with patch clamp electrophysiology. We demonstrate a new modulatory role of the β subunit on ethanol sensitivity of α2 subunits. Specifically, we found a differential allosteric modulation in homomeric α2 GlyRs compared with the α2β heteromeric conformation. Indeed, while α2 was insensitive, α2β GlyRs were substantially potentiated by ethanol, GTP-γ-S, propofol, Zn2+ and trichloroethanol. Furthermore, a Gβγ scavenger (ct-GRK2) selectively attenuated the effects of ethanol on recombinant α2β GlyRs. Mutations in an α2 GlyR co-expressed with the β subunit (α2AAβ) specifically blocked ethanol sensitivity, but not propofol potentiation. These results show a selective mechanism for low ethanol concentration effects on homomeric and heteromeric conformations of α2 GlyRs and provide a new mechanism for ethanol pharmacology, which is relevant to upper brain regions where α2 GlyRs are abundantly expressed.
format	article
author	Braulio Muñoz Trinidad Mariqueo Pablo Murath Christian Peters Gonzalo E. Yevenes Gustavo Moraga-Cid Robert W. Peoples Luis G. Aguayo
author_facet	Braulio Muñoz Trinidad Mariqueo Pablo Murath Christian Peters Gonzalo E. Yevenes Gustavo Moraga-Cid Robert W. Peoples Luis G. Aguayo
author_sort	Braulio Muñoz
title	Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
title_short	Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
title_full	Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
title_fullStr	Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
title_full_unstemmed	Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
title_sort	modulatory actions of the glycine receptor β subunit on the positive allosteric modulation of ethanol in α2 containing receptors
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/a1e12b7b340445f3965359c8b8f2cef4
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Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors

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