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Article: Endothelin type B receptor promotes cofilin rod formation and dendritic loss in neurons by inducing oxidative stress and cofilin activation

TitleEndothelin type B receptor promotes cofilin rod formation and dendritic loss in neurons by inducing oxidative stress and cofilin activation
Authors
Keywordscofilin
dendrite
NADPH oxidase
oxidative stress
neurodegeneration
Issue Date2019
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2019, v. 294 n. 33, p. 12495-12506 How to Cite?
AbstractEndothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress– or cofilin activation–driven cofilin rod formation. Here, we demonstrate that exposure to 100 nM ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nM IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 μM VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nM FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.
Persistent Identifierhttp://hdl.handle.net/10722/287955
ISSN
2019 Impact Factor: 4.238
2015 SCImago Journal Rankings: 3.151
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorTAM, SW-
dc.contributor.authorFENG, R-
dc.contributor.authorLau, WKW-
dc.contributor.authorLaw, ACK-
dc.contributor.authorYeung, PKK-
dc.contributor.authorChung, SK-
dc.date.accessioned2020-10-05T12:05:42Z-
dc.date.available2020-10-05T12:05:42Z-
dc.date.issued2019-
dc.identifier.citationJournal of Biological Chemistry, 2019, v. 294 n. 33, p. 12495-12506-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/287955-
dc.description.abstractEndothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress– or cofilin activation–driven cofilin rod formation. Here, we demonstrate that exposure to 100 nM ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nM IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 μM VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nM FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.-
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistry-
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.-
dc.rightsThis research was originally published in the [Journal of Biological Chemistry]. Sze-Wah Tam, Rui Feng, Way Kwok-Wai Lau, Andrew Chi-Kin Law, Patrick Ka-Kit Yeung and Sookja Kim Chung. Title. Journal of Biological Chemistry. 2019; 294(33):12495-12506. © the American Society for Biochemistry and Molecular Biology or © the Author(s).-
dc.subjectcofilin-
dc.subjectdendrite-
dc.subjectNADPH oxidase-
dc.subjectoxidative stress-
dc.subjectneurodegeneration-
dc.titleEndothelin type B receptor promotes cofilin rod formation and dendritic loss in neurons by inducing oxidative stress and cofilin activation-
dc.typeArticle-
dc.identifier.emailLaw, ACK: acklaw@hku.hk-
dc.identifier.authorityLaw, ACK=rp00262-
dc.identifier.authorityChung, SK=rp00381-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1074/jbc.RA118.005155-
dc.identifier.pmid31248984-
dc.identifier.pmcidPMC6699845-
dc.identifier.scopuseid_2-s2.0-85070785317-
dc.identifier.scopuseid_2-s2.0-85070785317-
dc.identifier.hkuros315761-
dc.identifier.volume294-
dc.identifier.issue33-
dc.identifier.spage12495-
dc.identifier.epage12506-
dc.publisher.placeUnited States-

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