Mutant SOD1 protein increases Na(v)1.3 channel excitability

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dc.contributor.authorKubat Öktem, Elif
dc.contributor.authorMruk, Karen
dc.contributor.authorChang, Joshua
dc.contributor.authorAkın, Ata
dc.contributor.authorKobertz, William R.
dc.contributor.authorBrown, Robert H., Jr.
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:57:26Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T19:57:26Z
dc.date.issued2016
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.descriptionWOS: 000379922500004
dc.descriptionPubMed ID: 27072680
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a lethal paralytic disease caused by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) are present in similar to 20% of familial ALS and similar to 2% of all ALS cases. The most common SOD1 gene mutation in North America is a missense mutation substituting valine for alanine (A4V). In this study, we analyze sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein. We demonstrate that the A4V mutation confers a propensity to hyperexcitability on a voltage-dependent sodium channel (Na(v)1.3) mediated by heightened total Na+ conductance and a hyperpolarizing shift in the voltage dependence of Na(v)1.3 activation. To estimate the impact of these channel effects on excitability in an intact neuron, we simulated these changes in the program NEURON; this shows that the changes induced by mutant SOD1 increase the spontaneous firing frequency of the simulated neuron. These findings are consistent with the view that excessive excitability of neurons is one component in the pathogenesis of this disease.
dc.description.sponsorshipAngel Fund; ALS Therapy; Project ALS; P2ALS; Pierre L. De Bourgknecht ALS Research Fund; National Institute of Neurological Disorders and Stroke (NINDS) [1RC2NS070342-01, 1RC1NS068391-01, R01NS050557-05, R01NS065847-01A1]en_US
dc.description.sponsorshipThis study was supported by the Angel Fund, the ALS Therapy, Project ALS, P2ALS, the Pierre L. De Bourgknecht ALS Research Fund, and the National Institute of Neurological Disorders and Stroke (NINDS) awards 1RC2NS070342-01, 1RC1NS068391-01, R01NS050557-05, and R01NS065847-01A1. We thank David Paydarfar for comments on the manuscript, Daryl Bosco for providing purified WT and mutant (A4V) human SOD1 protein, and Nick Wightman for assistance with Western immunoblotting.en_US
dc.identifier.citationKubat Öktem, E., Mruk, K., Chang, J., Akın, A., Kobertz, W. R. ve Brown, Robert H., Jr. (2016). Mutant SOD1 protein increases Na(v)1.3 channel excitability. Journal of Biological Physics, 42(3), 351-370. https://dx.doi.org/10.1007/s10867-016-9411-x
dc.identifier.doi10.1007/s10867-016-9411-x
dc.identifier.endpage370
dc.identifier.issn0092-0606
dc.identifier.issn1573-0689
dc.identifier.issue3
dc.identifier.scopusqualityQ2
dc.identifier.startpage351
dc.identifier.urihttps://dx.doi.org/10.1007/s10867-016-9411-x
dc.identifier.urihttps://hdl.handle.net/20.500.12511/2974
dc.identifier.volume42
dc.identifier.wosqualityQ4
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherSpringer
dc.relation.ispartofJournal of Biological Physicsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectNa-v Channel
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectHyperexcitability
dc.subjectSuperoxide Dismutase
dc.subjectOocyte
dc.titleMutant SOD1 protein increases Na(v)1.3 channel excitability
dc.typeArticle

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