Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion

In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in mi...

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Autores: Gerzanich, Volodymyr, Stokum, Jesse A., Ivanova, Svetlana, Woo, Seung Kyoon, Tsymbalyuk, Orest, Sharma, Amit, Akkentli, Fatih, Imran, Ziyan, Aarabi, Bizhan, Sahuquillo Barris, Juan|||0000-0003-0713-5875, Simard, J. Marc|||0000-0002-5373-1988
Formato: artículo
Fecha de publicación:2019
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:228001
Acesso em linha:https://ddd.uab.cat/record/228001
https://dx.doi.org/urn:doi:10.1089/neu.2018.5986
Access Level:acceso abierto
Palavra-chave:Brain contusion
Brain swelling
Glibenclamide
Hemorrhagic progression of contusion
K
SUR1-TRPM4
Traumatic brain injury
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spelling Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of ContusionGerzanich, VolodymyrStokum, Jesse A.Ivanova, SvetlanaWoo, Seung KyoonTsymbalyuk, OrestSharma, AmitAkkentli, FatihImran, ZiyanAarabi, BizhanSahuquillo Barris, Juan|||0000-0003-0713-5875Simard, J. Marc|||0000-0002-5373-1988Brain contusionBrain swellingGlibenclamideHemorrhagic progression of contusionKSUR1-TRPM4Traumatic brain injuryIn severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form K (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and K after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide.Universitat Autònoma de Barcelona 22019-01-0120192019-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/228001https://dx.doi.org/urn:doi:10.1089/neu.2018.5986reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2280012026-06-06T12:50:31Z
dc.title.none.fl_str_mv Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
title Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
spellingShingle Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
Gerzanich, Volodymyr
Brain contusion
Brain swelling
Glibenclamide
Hemorrhagic progression of contusion
K
SUR1-TRPM4
Traumatic brain injury
title_short Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
title_full Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
title_fullStr Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
title_full_unstemmed Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
title_sort Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion
dc.creator.none.fl_str_mv Gerzanich, Volodymyr
Stokum, Jesse A.
Ivanova, Svetlana
Woo, Seung Kyoon
Tsymbalyuk, Orest
Sharma, Amit
Akkentli, Fatih
Imran, Ziyan
Aarabi, Bizhan
Sahuquillo Barris, Juan|||0000-0003-0713-5875
Simard, J. Marc|||0000-0002-5373-1988
author Gerzanich, Volodymyr
author_facet Gerzanich, Volodymyr
Stokum, Jesse A.
Ivanova, Svetlana
Woo, Seung Kyoon
Tsymbalyuk, Orest
Sharma, Amit
Akkentli, Fatih
Imran, Ziyan
Aarabi, Bizhan
Sahuquillo Barris, Juan|||0000-0003-0713-5875
Simard, J. Marc|||0000-0002-5373-1988
author_role author
author2 Stokum, Jesse A.
Ivanova, Svetlana
Woo, Seung Kyoon
Tsymbalyuk, Orest
Sharma, Amit
Akkentli, Fatih
Imran, Ziyan
Aarabi, Bizhan
Sahuquillo Barris, Juan|||0000-0003-0713-5875
Simard, J. Marc|||0000-0002-5373-1988
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Brain contusion
Brain swelling
Glibenclamide
Hemorrhagic progression of contusion
K
SUR1-TRPM4
Traumatic brain injury
topic Brain contusion
Brain swelling
Glibenclamide
Hemorrhagic progression of contusion
K
SUR1-TRPM4
Traumatic brain injury
description In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form K (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and K after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide.
publishDate 2019
dc.date.none.fl_str_mv 2
2019-01-01
2019
2019-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/228001
https://dx.doi.org/urn:doi:10.1089/neu.2018.5986
url https://ddd.uab.cat/record/228001
https://dx.doi.org/urn:doi:10.1089/neu.2018.5986
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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