PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphoryla...
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| Veröffentlicht in: | International journal of molecular sciences 2020-08, Vol.21 (16), p.5643 |
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| creator | Kim, Ji-Eun Park, Hana Lee, Ji-Eun Kim, Tae-Hyun Kang, Tae-Cheon |
| description | α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists. |
| doi_str_mv | 10.3390/ijms21165643 |
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The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21165643</identifier><identifier>PMID: 32781725</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT1 protein ; Animals ; Benzodiazepines - pharmacology ; Benzodiazepines - therapeutic use ; Bisperoxovanadium ; Chromosome 10 ; Chromosomes ; Chronic Disease ; Convulsions & seizures ; Down-Regulation - drug effects ; Epilepsy ; Epilepsy - drug therapy ; Epilepsy - metabolism ; Hippocampus ; Hippocampus - metabolism ; Homology ; Ion channels ; Ion channels (ligand-gated) ; Kinases ; Male ; Models, Biological ; NF-kappa B - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Phosphorylation - drug effects ; Proto-Oncogene Proteins c-akt - metabolism ; PTEN Phosphohydrolase - antagonists & inhibitors ; PTEN Phosphohydrolase - metabolism ; PTEN protein ; Pyridones - pharmacology ; Pyridones - therapeutic use ; Rats, Sprague-Dawley ; Receptors, AMPA - antagonists & inhibitors ; Recording sessions ; Rodents ; Seizures ; Tensin ; Up-Regulation - drug effects ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><ispartof>International journal of molecular sciences, 2020-08, Vol.21 (16), p.5643</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). 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The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT1 protein</subject><subject>Animals</subject><subject>Benzodiazepines - pharmacology</subject><subject>Benzodiazepines - therapeutic use</subject><subject>Bisperoxovanadium</subject><subject>Chromosome 10</subject><subject>Chromosomes</subject><subject>Chronic Disease</subject><subject>Convulsions & seizures</subject><subject>Down-Regulation - drug effects</subject><subject>Epilepsy</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - metabolism</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Homology</subject><subject>Ion channels</subject><subject>Ion channels (ligand-gated)</subject><subject>Kinases</subject><subject>Male</subject><subject>Models, Biological</subject><subject>NF-kappa B - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>PTEN Phosphohydrolase - antagonists & inhibitors</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>PTEN protein</subject><subject>Pyridones - pharmacology</subject><subject>Pyridones - therapeutic use</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, AMPA - antagonists & inhibitors</subject><subject>Recording sessions</subject><subject>Rodents</subject><subject>Seizures</subject><subject>Tensin</subject><subject>Up-Regulation - drug effects</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpVkc1LAzEQxYMotlZvniXg1dV8bJLdi1DKqgU_SqnnkM0mbUq72ya7gv-9kdZST5nwfvNmhgfANUb3lObowS3XgWDMGU_pCejjlJAEIS5Oj-oeuAhhiRChhOXnoEeJyLAgrA_sZFa8w3GAU7PtnDcVtI2Hs4WBw7p1SbFxK7NpnYaFtUa3ATYWDt8mw8jrKEQ2cmre1C5E0dVwtPDxE_lD51S14RKcWbUK5mr_DsDnUzEbvSSvH8_j0fA10SkmbVKZEiOLSsM5zqnFRlhmiFJVHstUWVXGS3ORGpZpzVCFM4EYZ9iynCAtBB2Ax53vpivXptKmbr1ayY13a-W_ZaOc_K_UbiHnzZcUKUcZzaLB7d7AN9vOhFYum87XcWdJUkq4yHLBI3W3o7RvQvDGHiZgJH9TkcepRPzmeKsD_BcD_QGeCoh6</recordid><startdate>20200806</startdate><enddate>20200806</enddate><creator>Kim, Ji-Eun</creator><creator>Park, Hana</creator><creator>Lee, Ji-Eun</creator><creator>Kim, Tae-Hyun</creator><creator>Kang, Tae-Cheon</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20200806</creationdate><title>PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats</title><author>Kim, Ji-Eun ; Park, Hana ; Lee, Ji-Eun ; Kim, Tae-Hyun ; Kang, Tae-Cheon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-deb10f0be66193f1e7f5e2aad91e74afab211974e58cc50d18705651f5920c773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT1 protein</topic><topic>Animals</topic><topic>Benzodiazepines - pharmacology</topic><topic>Benzodiazepines - therapeutic use</topic><topic>Bisperoxovanadium</topic><topic>Chromosome 10</topic><topic>Chromosomes</topic><topic>Chronic Disease</topic><topic>Convulsions & seizures</topic><topic>Down-Regulation - drug effects</topic><topic>Epilepsy</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy - metabolism</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Homology</topic><topic>Ion channels</topic><topic>Ion channels (ligand-gated)</topic><topic>Kinases</topic><topic>Male</topic><topic>Models, Biological</topic><topic>NF-kappa B - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>PTEN Phosphohydrolase - antagonists & inhibitors</topic><topic>PTEN Phosphohydrolase - metabolism</topic><topic>PTEN protein</topic><topic>Pyridones - pharmacology</topic><topic>Pyridones - therapeutic use</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, AMPA - antagonists & inhibitors</topic><topic>Recording sessions</topic><topic>Rodents</topic><topic>Seizures</topic><topic>Tensin</topic><topic>Up-Regulation - drug effects</topic><topic>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid</topic><topic>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Ji-Eun</creatorcontrib><creatorcontrib>Park, Hana</creatorcontrib><creatorcontrib>Lee, Ji-Eun</creatorcontrib><creatorcontrib>Kim, Tae-Hyun</creatorcontrib><creatorcontrib>Kang, Tae-Cheon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Ji-Eun</au><au>Park, Hana</au><au>Lee, Ji-Eun</au><au>Kim, Tae-Hyun</au><au>Kang, Tae-Cheon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2020-08-06</date><risdate>2020</risdate><volume>21</volume><issue>16</issue><spage>5643</spage><pages>5643-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>32781725</pmid><doi>10.3390/ijms21165643</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2020-08, Vol.21 (16), p.5643 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 1-Phosphatidylinositol 3-kinase AKT1 protein Animals Benzodiazepines - pharmacology Benzodiazepines - therapeutic use Bisperoxovanadium Chromosome 10 Chromosomes Chronic Disease Convulsions & seizures Down-Regulation - drug effects Epilepsy Epilepsy - drug therapy Epilepsy - metabolism Hippocampus Hippocampus - metabolism Homology Ion channels Ion channels (ligand-gated) Kinases Male Models, Biological NF-kappa B - metabolism Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Phosphorylation - drug effects Proto-Oncogene Proteins c-akt - metabolism PTEN Phosphohydrolase - antagonists & inhibitors PTEN Phosphohydrolase - metabolism PTEN protein Pyridones - pharmacology Pyridones - therapeutic use Rats, Sprague-Dawley Receptors, AMPA - antagonists & inhibitors Recording sessions Rodents Seizures Tensin Up-Regulation - drug effects α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors |
| title | PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats |
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