Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1
Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII,...
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| Veröffentlicht in: | Cellular Physiology and Biochemistry 2018-04, Vol.46 (1), p.160-177 |
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| creator | Gu, Juan Tian, Xin Wang, Wei Yang, Qin Lin, Peijia Ma, Yuanlin Xiong, Yan Xu, Demei Zhang, Yanke Yang, Yong Lu, Shanshan Lin, Zijun Luo, Jing Xiao, Fei Wang, Xuefeng |
| description | Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy. |
| doi_str_mv | 10.1159/000488419 |
| format | Article |
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GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.</description><identifier>ISSN: 1015-8987</identifier><identifier>EISSN: 1421-9778</identifier><identifier>DOI: 10.1159/000488419</identifier><identifier>PMID: 29587280</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>4-aminopyridine ; 4-Aminopyridine - pharmacology ; Adolescent ; Adult ; Animals ; Behavior ; Brain - metabolism ; Brain - pathology ; Brain research ; Carbazoles - pharmacology ; Carbazoles - therapeutic use ; Care and treatment ; CGKII ; Child ; Convulsions & seizures ; Cyclic GMP - analogs & derivatives ; Cyclic GMP - pharmacology ; Cyclic GMP-Dependent Protein Kinase Type II - antagonists & inhibitors ; Cyclic GMP-Dependent Protein Kinase Type II - metabolism ; Disease Models, Animal ; Drug resistance ; Epilepsy ; Epilepsy - chemically induced ; Epilepsy - drug therapy ; Epilepsy - pathology ; Evoked Potentials - drug effects ; Female ; GluA1 ; Health aspects ; Hippocampus - drug effects ; Hippocampus - metabolism ; Humans ; Male ; Neurosciences ; Original Paper ; Parahippocampal region ; Patients ; Physiological aspects ; Pilocarpine ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA - genetics ; Receptors, AMPA - metabolism ; Rodents ; Seizures (Medicine) ; Synapses ; Synaptic Transmission - drug effects ; Thionucleotides - pharmacology ; Up-Regulation ; Young Adult</subject><ispartof>Cellular Physiology and Biochemistry, 2018-04, Vol.46 (1), p.160-177</ispartof><rights>2018 The Author(s). Published by S. Karger AG, Basel</rights><rights>2018 The Author(s). Published by S. Karger AG, Basel.</rights><rights>COPYRIGHT 2018 S. Karger AG</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-4f82366adfdd26d3633efe4e2a96f61e93dda5993290fc1a7e9cae38c97653ba3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,2096,27612,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29587280$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gu, Juan</creatorcontrib><creatorcontrib>Tian, Xin</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Yang, Qin</creatorcontrib><creatorcontrib>Lin, Peijia</creatorcontrib><creatorcontrib>Ma, Yuanlin</creatorcontrib><creatorcontrib>Xiong, Yan</creatorcontrib><creatorcontrib>Xu, Demei</creatorcontrib><creatorcontrib>Zhang, Yanke</creatorcontrib><creatorcontrib>Yang, Yong</creatorcontrib><creatorcontrib>Lu, Shanshan</creatorcontrib><creatorcontrib>Lin, Zijun</creatorcontrib><creatorcontrib>Luo, Jing</creatorcontrib><creatorcontrib>Xiao, Fei</creatorcontrib><creatorcontrib>Wang, Xuefeng</creatorcontrib><title>Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1</title><title>Cellular Physiology and Biochemistry</title><addtitle>Cell Physiol Biochem</addtitle><description>Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.</description><subject>4-aminopyridine</subject><subject>4-Aminopyridine - pharmacology</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Animals</subject><subject>Behavior</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain research</subject><subject>Carbazoles - pharmacology</subject><subject>Carbazoles - therapeutic use</subject><subject>Care and treatment</subject><subject>CGKII</subject><subject>Child</subject><subject>Convulsions & seizures</subject><subject>Cyclic GMP - analogs & derivatives</subject><subject>Cyclic GMP - pharmacology</subject><subject>Cyclic GMP-Dependent Protein Kinase Type II - antagonists & inhibitors</subject><subject>Cyclic GMP-Dependent Protein Kinase Type II - metabolism</subject><subject>Disease Models, Animal</subject><subject>Drug resistance</subject><subject>Epilepsy</subject><subject>Epilepsy - chemically induced</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - pathology</subject><subject>Evoked Potentials - drug effects</subject><subject>Female</subject><subject>GluA1</subject><subject>Health aspects</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Neurosciences</subject><subject>Original Paper</subject><subject>Parahippocampal region</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Pilocarpine</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, AMPA - genetics</subject><subject>Receptors, AMPA - metabolism</subject><subject>Rodents</subject><subject>Seizures (Medicine)</subject><subject>Synapses</subject><subject>Synaptic Transmission - drug effects</subject><subject>Thionucleotides - pharmacology</subject><subject>Up-Regulation</subject><subject>Young Adult</subject><issn>1015-8987</issn><issn>1421-9778</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>M--</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNpdkstv1DAQxiMEog84cEfIEpdy2OJH4sdxtZR2pUogCufIscept9k42ElF4J_H2132gHywZ_T7vpmRpyjeEHxJSKU-YoxLKUuinhWnpKRkoYSQz_Mbk2ohlRQnxVlKG5xDoejL4oSqSgoq8WnxZ93f-8aPPvQoOLRqH7xHd9MwREgJEroD_3uKgJZm9I9-nJHuLbrxwxCM3g66Q1e_jB_1k76Z0Tdopy5HfYvGe0BfQxrT3Oth9AZ9gs4_Qpx3da67SZNXxQunuwSvD_d58ePz1ffVzeL2y_V6tbxdmArTcVE6SRnn2jprKbeMMwYOSqBacccJKGatrpRiVGFniBagjAYmjRK8Yo1m58V672uD3tRD9Fsd5zpoXz8lQmxrHXOHHdTcOMWtMFw6UzZUKKUoaTiUDYgmV8teF3uvIYafE6Sx3vpkoOt0D2FKNcVElULikmT0_X_oJkyxz5PWlBBBOFNqZ3i5p1qd6_vehTFqk4-FrTehB-dzfsmZqCiTimXBh73AxJBSBHeciOB6tw71cR0y--7QwtRswR7Jf_-fgbd74EHHFuIROOj_Avs4uPk</recordid><startdate>20180401</startdate><enddate>20180401</enddate><creator>Gu, Juan</creator><creator>Tian, Xin</creator><creator>Wang, Wei</creator><creator>Yang, Qin</creator><creator>Lin, Peijia</creator><creator>Ma, Yuanlin</creator><creator>Xiong, Yan</creator><creator>Xu, Demei</creator><creator>Zhang, Yanke</creator><creator>Yang, Yong</creator><creator>Lu, Shanshan</creator><creator>Lin, Zijun</creator><creator>Luo, Jing</creator><creator>Xiao, Fei</creator><creator>Wang, Xuefeng</creator><general>S. Karger AG</general><general>Cell Physiol Biochem Press GmbH & Co KG</general><scope>M--</scope><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>IAO</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>DOA</scope></search><sort><creationdate>20180401</creationdate><title>Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1</title><author>Gu, Juan ; Tian, Xin ; Wang, Wei ; Yang, Qin ; Lin, Peijia ; Ma, Yuanlin ; Xiong, Yan ; Xu, Demei ; Zhang, Yanke ; Yang, Yong ; Lu, Shanshan ; Lin, Zijun ; Luo, Jing ; Xiao, Fei ; Wang, Xuefeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-4f82366adfdd26d3633efe4e2a96f61e93dda5993290fc1a7e9cae38c97653ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>4-aminopyridine</topic><topic>4-Aminopyridine - 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metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Neurosciences</topic><topic>Original Paper</topic><topic>Parahippocampal region</topic><topic>Patients</topic><topic>Physiological aspects</topic><topic>Pilocarpine</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, AMPA - genetics</topic><topic>Receptors, AMPA - metabolism</topic><topic>Rodents</topic><topic>Seizures (Medicine)</topic><topic>Synapses</topic><topic>Synaptic Transmission - drug effects</topic><topic>Thionucleotides - pharmacology</topic><topic>Up-Regulation</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gu, Juan</creatorcontrib><creatorcontrib>Tian, Xin</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Yang, Qin</creatorcontrib><creatorcontrib>Lin, Peijia</creatorcontrib><creatorcontrib>Ma, Yuanlin</creatorcontrib><creatorcontrib>Xiong, Yan</creatorcontrib><creatorcontrib>Xu, Demei</creatorcontrib><creatorcontrib>Zhang, Yanke</creatorcontrib><creatorcontrib>Yang, Yong</creatorcontrib><creatorcontrib>Lu, Shanshan</creatorcontrib><creatorcontrib>Lin, Zijun</creatorcontrib><creatorcontrib>Luo, Jing</creatorcontrib><creatorcontrib>Xiao, Fei</creatorcontrib><creatorcontrib>Wang, Xuefeng</creatorcontrib><collection>Karger Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale Academic OneFile</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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical 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>MEDLINE - Academic</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Cellular Physiology and Biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gu, Juan</au><au>Tian, Xin</au><au>Wang, Wei</au><au>Yang, Qin</au><au>Lin, Peijia</au><au>Ma, Yuanlin</au><au>Xiong, Yan</au><au>Xu, Demei</au><au>Zhang, Yanke</au><au>Yang, Yong</au><au>Lu, Shanshan</au><au>Lin, Zijun</au><au>Luo, Jing</au><au>Xiao, Fei</au><au>Wang, Xuefeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1</atitle><jtitle>Cellular Physiology and Biochemistry</jtitle><addtitle>Cell Physiol Biochem</addtitle><date>2018-04-01</date><risdate>2018</risdate><volume>46</volume><issue>1</issue><spage>160</spage><epage>177</epage><pages>160-177</pages><issn>1015-8987</issn><eissn>1421-9778</eissn><abstract>Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>29587280</pmid><doi>10.1159/000488419</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 4-aminopyridine 4-Aminopyridine - pharmacology Adolescent Adult Animals Behavior Brain - metabolism Brain - pathology Brain research Carbazoles - pharmacology Carbazoles - therapeutic use Care and treatment CGKII Child Convulsions & seizures Cyclic GMP - analogs & derivatives Cyclic GMP - pharmacology Cyclic GMP-Dependent Protein Kinase Type II - antagonists & inhibitors Cyclic GMP-Dependent Protein Kinase Type II - metabolism Disease Models, Animal Drug resistance Epilepsy Epilepsy - chemically induced Epilepsy - drug therapy Epilepsy - pathology Evoked Potentials - drug effects Female GluA1 Health aspects Hippocampus - drug effects Hippocampus - metabolism Humans Male Neurosciences Original Paper Parahippocampal region Patients Physiological aspects Pilocarpine Rats Rats, Sprague-Dawley Receptors, AMPA - genetics Receptors, AMPA - metabolism Rodents Seizures (Medicine) Synapses Synaptic Transmission - drug effects Thionucleotides - pharmacology Up-Regulation Young Adult |
| title | Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1 |
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