Genetic inactivation of the sigma-1 chaperone protein results in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures

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dc.contributor.authorVavers, Edijs
dc.contributor.authorZvejniece, Baiba
dc.contributor.authorStelfa, Gundega
dc.contributor.authorSvalbe, Baiba
dc.contributor.authorVilks, Karlis
dc.contributor.authorKupats, Einars
dc.contributor.authorMezapuke, Rudolfs
dc.contributor.authorLauberte, Lasma
dc.contributor.authorDambrova, Maija
dc.contributor.authorZvejniece, Liga
dc.contributor.institutionRīga Stradiņš University
dc.date.accessioned2021-04-27T13:35:02Z
dc.date.available2021-04-27T13:35:02Z
dc.date.issued2021-03-01
dc.descriptionFunding Information: This study was supported by European Regional Development Fund Project No. 1.1.1.2/VIAA/2/18/376 (PostDoc Latvia), “Sigma chaperone protein as a novel drug target”. We thank Laboratorios Dr. Esteve, S.A. (Barcelona, Spain) for providing CD-1 background sigma-1 receptor knockout mice. We thank Associate Professors Inga Kadisha and Thomas van Groen (University of Alabama at Birmingham, Birmingham, Alabama, USA) for fruitful discussions regarding immunohistochemistry. We also thank Dr. biol. Dace Pjanova (Latvian Biomedical Research and Study Centre, Riga, Latvia) for the help with confocal imaging and Abberior Instruments (Göttingen, Germany) for a kind gift of fluorescently labeled Abberior STAR antibodies. Publisher Copyright: © 2020 The Author(s)
dc.description.abstractThere is a growing body of evidence demonstrating the significant involvement of the sigma-1 chaperone protein in the modulation of seizures. Several sigma-1 receptor (Sig1R) ligands have been demonstrated to regulate the seizure threshold in acute and chronic seizure models. However, the mechanism by which Sig1R modulates the excitatory and inhibitory pathways in the brain has not been elucidated. The aim of this study was to compare the susceptibility to seizures of wild type (WT) and Sig1R knockout (Sig1R−/−) mice in intravenous pentylenetetrazol (PTZ) and (+)-bicuculline (BIC) infusion-induced acute seizure and Sig1R antagonist NE-100-induced seizure models. To determine possible molecular mechanisms, we used quantitative PCR, Western blotting and immunohistochemistry to assess the possible involvement of several seizure-related genes and proteins. Peripheral tissue contractile response of WT and Sig1R−/− mice was studied in an isolated vasa deferentia model. The most important finding was the significantly decreased expression of the R2 subunit of the GABA-B receptor in the hippocampus and habenula of Sig1R−/− mice. Our results demonstrated that Sig1R−/− mice have decreased thresholds for PTZ- and BIC-induced tonic seizures. In the NE-100-induced seizure model, Sig1R−/− animals demonstrated lower seizure scores, shorter durations and increased latency times of seizures compared to WT mice. Sig1R-independent activities of NE-100 included downregulation of the gene expression of iNOS and GABA-A γ2 and inhibition of KCl-induced depolarization in both WT and Sig1R−/− animals. In conclusion, the results of this study indicate that the lack of Sig1R resulted in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures. Our results confirm that Sig1R is a significant molecular target for seizure modulation and warrants further investigation for the development of novel anti-seizure drugs.en
dc.description.statusPeer reviewed
dc.format.extent8771263
dc.identifier.citationVavers, E, Zvejniece, B, Stelfa, G, Svalbe, B, Vilks, K, Kupats, E, Mezapuke, R, Lauberte, L, Dambrova, M & Zvejniece, L 2021, 'Genetic inactivation of the sigma-1 chaperone protein results in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures', Neurobiology of Disease, vol. 150, 105244. https://doi.org/10.1016/j.nbd.2020.105244
dc.identifier.doi10.1016/j.nbd.2020.105244
dc.identifier.issn0969-9961
dc.identifier.otherMendeley: 35391a72-2652-3f5f-a136-1cbe612e2a2e
dc.identifier.otherunpaywall: 10.1016/j.nbd.2020.105244
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/3945
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85098960898&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofNeurobiology of Disease
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGABA-B receptor
dc.subjectKnockout
dc.subjectMedial habenula
dc.subjectNE-100
dc.subjectSeizures
dc.subjectSigma-1 receptor
dc.subject3.1 Basic medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectNeurology
dc.titleGenetic inactivation of the sigma-1 chaperone protein results in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizuresen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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