{"author":[{"first_name":"Jerome","last_name":"Clatot","full_name":"Clatot, Jerome"},{"orcid":"0000-0002-4809-5059","last_name":"Currin","first_name":"Christopher","id":"e8321fc5-3091-11eb-8a53-83f309a11ac9","full_name":"Currin, Christopher"},{"last_name":"Liang","first_name":"Qiansheng","full_name":"Liang, Qiansheng"},{"first_name":"Tanadet","last_name":"Pipatpolkai","full_name":"Pipatpolkai, Tanadet"},{"full_name":"Massey, Shavonne L.","last_name":"Massey","first_name":"Shavonne L."},{"full_name":"Helbig, Ingo","first_name":"Ingo","last_name":"Helbig"},{"full_name":"Delemotte, Lucie","first_name":"Lucie","last_name":"Delemotte"},{"last_name":"Vogels","first_name":"Tim P","id":"CB6FF8D2-008F-11EA-8E08-2637E6697425","full_name":"Vogels, Tim P","orcid":"0000-0003-3295-6181"},{"first_name":"Manuel","last_name":"Covarrubias","full_name":"Covarrubias, Manuel"},{"first_name":"Ethan M.","last_name":"Goldberg","full_name":"Goldberg, Ethan M."}],"publication":"Proceedings of the National Academy of Sciences of the United States of America","doi":"10.1073/pnas.2307776121","publication_identifier":{"eissn":["1091-6490"]},"external_id":{"pmid":["38194456"]},"citation":{"short":"J. Clatot, C. Currin, Q. Liang, T. Pipatpolkai, S.L. Massey, I. Helbig, L. Delemotte, T.P. Vogels, M. Covarrubias, E.M. Goldberg, Proceedings of the National Academy of Sciences of the United States of America 121 (2024).","ista":"Clatot J, Currin C, Liang Q, Pipatpolkai T, Massey SL, Helbig I, Delemotte L, Vogels TP, Covarrubias M, Goldberg EM. 2024. A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction. Proceedings of the National Academy of Sciences of the United States of America. 121(3), e2307776121.","apa":"Clatot, J., Currin, C., Liang, Q., Pipatpolkai, T., Massey, S. L., Helbig, I., … Goldberg, E. M. (2024). A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. Proceedings of the National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2307776121\">https://doi.org/10.1073/pnas.2307776121</a>","chicago":"Clatot, Jerome, Christopher Currin, Qiansheng Liang, Tanadet Pipatpolkai, Shavonne L. Massey, Ingo Helbig, Lucie Delemotte, Tim P Vogels, Manuel Covarrubias, and Ethan M. Goldberg. “A Structurally Precise Mechanism Links an Epilepsy-Associated KCNC2 Potassium Channel Mutation to Interneuron Dysfunction.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. Proceedings of the National Academy of Sciences, 2024. <a href=\"https://doi.org/10.1073/pnas.2307776121\">https://doi.org/10.1073/pnas.2307776121</a>.","ama":"Clatot J, Currin C, Liang Q, et al. A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2024;121(3). doi:<a href=\"https://doi.org/10.1073/pnas.2307776121\">10.1073/pnas.2307776121</a>","ieee":"J. Clatot <i>et al.</i>, “A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 3. Proceedings of the National Academy of Sciences, 2024.","mla":"Clatot, Jerome, et al. “A Structurally Precise Mechanism Links an Epilepsy-Associated KCNC2 Potassium Channel Mutation to Interneuron Dysfunction.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 3, e2307776121, Proceedings of the National Academy of Sciences, 2024, doi:<a href=\"https://doi.org/10.1073/pnas.2307776121\">10.1073/pnas.2307776121</a>."},"article_type":"original","ec_funded":1,"_id":"14841","article_number":"e2307776121","language":[{"iso":"eng"}],"volume":121,"intvolume":"       121","year":"2024","acknowledgement":"This work was supported by an ERC Consolidator Grant (SYNAPSEEK) to T.P.V., the NOMIS Foundation through the NOMIS Fellowships program at IST Austria to C.B.C., a Jefferson Synaptic Biology Center Pilot Project Grant to M.C., NIH NINDS U54 NS108874 (PI, Alfred L. George), and NIH NINDS R01 NS122887 to E.M.G. The computations were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at the PDC Center for High-Performance Computing, KTH Royal Institute of Technology, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. We thank Akshay Sridhar for the fruitful discussion of the project.","project":[{"call_identifier":"H2020","_id":"0aacfa84-070f-11eb-9043-d7eb2c709234","name":"Learning the shape of synaptic plasticity rules for neuronal architectures and function through machine learning.","grant_number":"819603"}],"day":"16","type":"journal_article","pmid":1,"date_updated":"2024-01-23T10:20:40Z","article_processing_charge":"No","month":"01","issue":"3","publication_status":"published","date_published":"2024-01-16T00:00:00Z","abstract":[{"text":"De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.","lang":"eng"}],"department":[{"_id":"TiVo"}],"date_created":"2024-01-21T23:00:56Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa_version":"None","scopus_import":"1","publisher":"Proceedings of the National Academy of Sciences","status":"public","related_material":{"link":[{"relation":"software","url":"https://github.com/ChrisCurrin/pv-kcnc2 "}]},"quality_controlled":"1","title":"A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction"}