Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation
Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ<sub>42</sub> oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiolo...
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| Format: | Article |
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2022-09-01
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| author | Irina Yu. Petrushanko Artem M. Tverskoi Evgeny P. Barykin Aleksandra V. Petrovskaya Maria A. Strelkova Olga G. Leonova Anastasia A. Anashkina Anna P. Tolstova Alexei A. Adzhubei Anna Yu. Bogdanova Alexander A. Makarov Vladimir A. Mitkevich |
| author_facet | Irina Yu. Petrushanko Artem M. Tverskoi Evgeny P. Barykin Aleksandra V. Petrovskaya Maria A. Strelkova Olga G. Leonova Anastasia A. Anashkina Anna P. Tolstova Alexei A. Adzhubei Anna Yu. Bogdanova Alexander A. Makarov Vladimir A. Mitkevich |
| author_sort | Irina Yu. Petrushanko |
| collection | DOAJ |
| description | Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ<sub>42</sub> oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ<sub>42</sub> interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ<sub>42</sub> monomer, triggering Src kinase activation. The co-localization of Aβ<sub>42</sub> with α1- and β1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aβ<sub>42</sub> causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ<sub>42</sub> with α1β1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aβ-induced Src kinase activation. Stimulatory effect of Aβ<sub>42</sub> on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aβ<sub>42</sub> receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ<sub>42</sub> in the nervous system. |
| first_indexed | 2024-03-10T01:56:15Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:56:15Z |
| publishDate | 2022-09-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-b59b71b531fe4e4fb32469fb7869285c2023-11-23T12:56:23ZengMDPI AGCells2073-44092022-09-011117275310.3390/cells11172753Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase ActivationIrina Yu. Petrushanko0Artem M. Tverskoi1Evgeny P. Barykin2Aleksandra V. Petrovskaya3Maria A. Strelkova4Olga G. Leonova5Anastasia A. Anashkina6Anna P. Tolstova7Alexei A. Adzhubei8Anna Yu. Bogdanova9Alexander A. Makarov10Vladimir A. Mitkevich11Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaInstitute of Veterinary Physiology, Vetsuisse Faculty and the Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, CH-8057 Zurich, SwitzerlandEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaBeta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ<sub>42</sub> oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ<sub>42</sub> interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ<sub>42</sub> monomer, triggering Src kinase activation. The co-localization of Aβ<sub>42</sub> with α1- and β1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aβ<sub>42</sub> causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ<sub>42</sub> with α1β1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aβ-induced Src kinase activation. Stimulatory effect of Aβ<sub>42</sub> on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aβ<sub>42</sub> receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ<sub>42</sub> in the nervous system.https://www.mdpi.com/2073-4409/11/17/2753Na,K-ATPasebeta-amyloidSrc kinasehypoxiareceptor function |
| spellingShingle | Irina Yu. Petrushanko Artem M. Tverskoi Evgeny P. Barykin Aleksandra V. Petrovskaya Maria A. Strelkova Olga G. Leonova Anastasia A. Anashkina Anna P. Tolstova Alexei A. Adzhubei Anna Yu. Bogdanova Alexander A. Makarov Vladimir A. Mitkevich Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation Cells Na,K-ATPase beta-amyloid Src kinase hypoxia receptor function |
| title | Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation |
| title_full | Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation |
| title_fullStr | Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation |
| title_full_unstemmed | Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation |
| title_short | Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation |
| title_sort | na k atpase acts as a beta amyloid receptor triggering src kinase activation |
| topic | Na,K-ATPase beta-amyloid Src kinase hypoxia receptor function |
| url | https://www.mdpi.com/2073-4409/11/17/2753 |
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