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Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel
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Cloxyquin has been reported as a specific activator of TRESK (K2P18.1, TWIK-related spinal cord K+ channel) background potassium channel. In this study, we have synthetized chemically modified analogues of cloxyquin and tested their effects on TRESK and other K2P channels. The currents of murine K2P channels, expressed heterologously in Xenopus oocytes, were measured by two-electrode voltage clamp, whereas the native background K+ conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell patch clamp method. Some of the analogues retained the activator character of the parent compound, but more interestingly, other derivatives inhibited mouse TRESK current. The inhibitor analogues (A2764 and A2793) exerted state-dependent effect. The degree of inhibition by 100 µM A2764 (77.8±1.5%, n=6) was larger in the activated state of TRESK (i.e. after calcineurin-dependent stimulation) than in the resting state of the channel (42.8±4.3% inhibition, n=7). The selectivity of the inhibitor compounds was tested on several K2P channels. A2793 inhibited TASK-1 (100 µM, 53.4±6%, n=5), while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and TALK-1. The effect of A2764 was also examined on the background K+ currents of DRG neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed background K+ currents sensitive to A2764, while the inhibitor did not affect the currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove to be useful for the identification of TRESK current in native cells, and for the investigation of the role of the channel in nociception and migraine.
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<div class="JournalArticle Publication short-list"> <div class="authors"> <span class="author-name" mtid="10053920"> <a href="/gui2/?type=authors&mode=browse&sel=10053920" target="_blank">Lengyel, Miklos</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="129"> <a href="/gui2/?type=authors&mode=browse&sel=129" target="_blank">Erdelyi, Ferenc</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10069271"> <a href="/gui2/?type=authors&mode=browse&sel=10069271" target="_blank">Pergel, Eniko</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10002919"> <a href="/gui2/?type=authors&mode=browse&sel=10002919" target="_blank">Balint-Polonka, Agnes</a> </span> <span class="author-type"> </span> ; <span class="author-name" > Dobolyi, Alice </span> <span class="author-type"> </span> ; <span class="author-name" > Bozsaki, Peter </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10010455"> <a href="/gui2/?type=authors&mode=browse&sel=10010455" target="_blank">Dux, Maria</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10015480"> <a href="/gui2/?type=authors&mode=browse&sel=10015480" target="_blank">Kiraly, Kornel</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10015687"> <a href="/gui2/?type=authors&mode=browse&sel=10015687" target="_blank">Hegedus, Tamas</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10013384"> <a href="/gui2/?type=authors&mode=browse&sel=10013384" target="_blank">Czirjak, Gabor</a> </span> <span class="author-type"> </span> et al. </div ><div class="title"><a href="/gui2/?mode=browse¶ms=publication;30654928" mtid="30654928" target="_blank">Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel</a></div> <div class="pub-info"> <span class="journal-title">MOLECULAR PHARMACOLOGY</span> <span class="journal-volume">95</span> : <span class="journal-issue">6</span> <span class="page"> pp. 652-660. , 9 p. </span> <span class="year">(2019)</span> </div> <div class="pub-end"><div class="identifier-list"> <span class="identifiers"> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="10.1124/mol.118.115626" target="_blank" href="https://doi.org/10.1124/mol.118.115626"> DOI </a> </span> <span class="id identifier oa_GREEN" title=" Green "> <a style="color:black" title="7003" target="_blank" href="https://repo.lib.semmelweis.hu/handle/123456789/7003"> SE Repozitórium </a> </span> <span class="id identifier oa_CLOSED" title=" Zárt "> <a style="color:black" title="102704" target="_blank" href="http://real.mtak.hu/102704"> REAL </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="000472623300007" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/000472623300007"> WoS </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="85066418023" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85066418023"> Scopus </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="30979812" target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=30979812&dopt=Abstract"> PubMed </a> </span> <span class="id identifier oa_GREEN" title=" Green "> <a style="color:blue" title="17627" target="_blank" href="http://publicatio.bibl.u-szeged.hu/17627"> SZTE Publicatio </a> </span> </span> </div> <div class="short-pub-prop-list"> <span class="deleted-record">Zárolt</span> <span class="short-pub-mtid"> Közlemény:30654928 </span> <span class="status-holder"><span class="status-data status-VALIDATED"> Egyeztetett </span></span> <span class="pub-core">Forrás Idéző </span> <span class="pub-type">Folyóiratcikk (Szakcikk ) </span> <!-- && !record.category.scientific --> <span class="pub-category">Tudományos</span> <div class="publication-citation" style="margin-left: 0.5cm;"> <span title="Nyilvános idézőközlemények összesen, említések nélkül" class="citingPub-count">Nyilvános idéző összesen: 10</span> | Független: 7 | Függő: 3 | Nem jelölt: 0 | WoS jelölt: 9 | Scopus jelölt: 10 | WoS/Scopus jelölt: 10 | DOI jelölt: 10 </div> </div> </div> </div><div class="JournalArticle Publication long-list"> <div class="authors"> <img title="Forrásközlemény" style="float: left" src="/frontend/resources/grid/publication-core-icon.png"> <img title="Idézőközlemény" style="float: left" src="/frontend/resources/grid/publication-citation-icon.png"> <div class="autype autype0"> <span class="author-name" mtid="10053920"><a href="/gui2/?type=authors&mode=browse&sel=10053920" target="_blank">Lengyel Miklos (<span class="authorship-author-name">Lengyel Miklós</span> <span class="authorAux-mtmt"> Biokémia</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Általános Orvostudományi Kar">AOK</span>/<span title="Intézet">I</span>/Élettani Intézet</span> ; <span class="author-name" mtid="129"><a href="/gui2/?type=authors&mode=browse&sel=129" target="_blank">Erdelyi Ferenc (<span class="authorship-author-name">Erdélyi Ferenc</span> <span class="authorAux-mtmt"> Molekuláris biológia, genetika</span>) </a> </span> <span class="author-affil">MTA Kísérleti Orvostudományi Kutatóintézet</span> ; <span class="author-name" mtid="10069271"><a href="/gui2/?type=authors&mode=browse&sel=10069271" target="_blank">Pergel Eniko (<span class="authorship-author-name">Pergel Enikő</span> <span class="authorAux-mtmt"> Molekuláris biológia</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Általános Orvostudományi Kar">AOK</span>/<span title="Intézet">I</span>/Élettani Intézet</span> ; <span class="author-name" mtid="10002919"><a href="/gui2/?type=authors&mode=browse&sel=10002919" target="_blank">Balint-Polonka Agnes (<span class="authorship-author-name">Polonkáné Bálint Ágnes</span> <span class="authorAux-mtmt"> Szerves kémia, heterociklusos kémia</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Gyógyszerésztudományi Kar">GYTK</span>/Szerves Vegytani Intézet</span> ; <span class="author-name" >Dobolyi Alice </span> ; <span class="author-name" >Bozsaki Peter </span> ; <span class="author-name" mtid="10010455"><a href="/gui2/?type=authors&mode=browse&sel=10010455" target="_blank">Dux Maria (<span class="authorship-author-name">Dux Mária</span> <span class="authorAux-mtmt"> élettan</span>) </a> </span> <span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Általános Orvostudományi Kar">ÁOK</span>/Élettani Intézet</span> ; <span class="author-name" mtid="10015480"><a href="/gui2/?type=authors&mode=browse&sel=10015480" target="_blank">Kiraly Kornel (<span class="authorship-author-name">Király Kornél P</span> <span class="authorAux-mtmt"> Farmakológia</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Általános Orvostudományi Kar">AOK</span>/<span title="Intézet">I</span>/Farmakológiai és Farmakoterápiás Intézet</span> ; <span class="author-name" mtid="10015687"><a href="/gui2/?type=authors&mode=browse&sel=10015687" target="_blank">Hegedus Tamas (<span class="authorship-author-name">Hegedűs Tamás</span> <span class="authorAux-mtmt"> bioinformatika, biofizika</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Általános Orvostudományi Kar">AOK</span>/<span title="Intézet">I</span>/Biofizikai és Sugárbiológiai Intézet</span> ; <span class="author-name" mtid="10013384"><a href="/gui2/?type=authors&mode=browse&sel=10013384" target="_blank">Czirjak Gabor (<span class="authorship-author-name">Czirják Gábor</span> <span class="authorAux-mtmt"> Élettan</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Általános Orvostudományi Kar">AOK</span>/<span title="Intézet">I</span>/Élettani Intézet</span> ; <span class="author-name" mtid="10007438"><a href="/gui2/?type=authors&mode=browse&sel=10007438" target="_blank">Matyus Peter (<span class="authorship-author-name">Mátyus Péter</span> <span class="authorAux-mtmt"> Szerves- és gyógyszerkémia</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Gyógyszerésztudományi Kar">GYTK</span>/Szerves Vegytani Intézet</span> ; <span class="author-name" mtid="10007806"><a href="/gui2/?type=authors&mode=browse&sel=10007806" target="_blank">Enyedi Peter ✉ (<span class="authorship-author-name">Enyedi Péter</span> <span class="authorAux-mtmt"> Biokémia</span>) </a> </span> <span class="author-affil"><span title="Semmelweis Egyetem">SE</span>/<span title="Általános Orvostudományi Kar">AOK</span>/<span title="Intézet">I</span>/Élettani Intézet</span> </div> </div> <div class="title"><a href="/gui2/?mode=browse¶ms=publication;30654928" target="_blank">Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel</a></div> <div> <span class="journal-title">MOLECULAR PHARMACOLOGY</span> <span class="journal-issn">(<a target="_blank" href="https://portal.issn.org/resource/ISSN/0026-895X">0026-895X</a> <a target="_blank" href="https://portal.issn.org/resource/ISSN/1521-0111">1521-0111</a>)</span>: <span class="journal-volume">95</span> <span class="journal-issue">6</span> <span class="page"> pp 652-660 </span> <span class="year">(2019)</span> </div> <div class="pub-footer"> <span class="language" xmlns="http://www.w3.org/1999/html">Nyelv: Angol | </span> <span class="identifiers"> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="10.1124/mol.118.115626" target="_blank" href="https://doi.org/10.1124/mol.118.115626"> DOI </a> </span> <span class="id identifier oa_GREEN" title=" Green "> <a style="color:black" title="7003" target="_blank" href="https://repo.lib.semmelweis.hu/handle/123456789/7003"> SE Repozitórium </a> </span> <span class="id identifier oa_CLOSED" title=" Zárt "> <a style="color:black" title="102704" target="_blank" href="http://real.mtak.hu/102704"> REAL </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="000472623300007" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/000472623300007"> WoS </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="85066418023" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85066418023"> Scopus </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="30979812" target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=30979812&dopt=Abstract"> PubMed </a> </span> <span class="id identifier oa_GREEN" title=" Green "> <a style="color:blue" title="17627" target="_blank" href="http://publicatio.bibl.u-szeged.hu/17627"> SZTE Publicatio </a> </span> </span> <div class="publication-citation" style="margin-left: 0.5cm;"> <span title="Nyilvános idézőközlemények összesen, említések nélkül" class="citingPub-count">Nyilvános idéző összesen: 10</span> | Független: 7 | Függő: 3 | Nem jelölt: 0 | WoS jelölt: 9 | Scopus jelölt: 10 | WoS/Scopus jelölt: 10 | DOI jelölt: 10 </div> <div class="publication-citation"> <a target="_blank" href="/api/publication?cond=citations.related;eq;30654928&sort=publishedYear,desc&sort=title"> Idézett közlemények száma: 8 </a> </div> <div class="mtid"><span class="long-pub-mtid">Közlemény: 30654928</span> | <span class="status-data status-VALIDATED"> Egyeztetett </span> Forrás Idéző | <span class="type-subtype">Folyóiratcikk ( Szakcikk ) </span> | <span class="pub-category">Tudományos</span> | <span class="publication-sourceOfData">PubMed (pubmed_result (3).xml, 2019-05-02)</span> </div> <div class="funder"> Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése(EFOP-3.6.3-VEKOP-16-2017-00009) Támogató: EFOP-VEKOP </div> <div class="lastModified">Utolsó módosítás: 2021.07.19. 18:28 Csajbók Edit (SE_KK_Admin5_CSE, admin) </div> <div class="lockedBy">Ideiglenesen zárolva 2022.07.08. 12:16 Boros Annamária (MTMT Központi admin) </div> </div></div>