000886070 001__ 886070
000886070 005__ 20210220152101.0
000886070 0247_ $$2doi$$a10.1111/bph.15196
000886070 0247_ $$2ISSN$$a0007-1188
000886070 0247_ $$2ISSN$$a0366-0826
000886070 0247_ $$2ISSN$$a1476-5381
000886070 0247_ $$2ISSN$$a2056-8177
000886070 0247_ $$2Handle$$a2128/26036
000886070 0247_ $$2altmetric$$aaltmetric:86186603
000886070 0247_ $$2pmid$$apmid:32663327
000886070 0247_ $$2WOS$$aWOS:000563939100001
000886070 037__ $$aFZJ-2020-04256
000886070 082__ $$a610
000886070 1001_ $$0P:(DE-HGF)0$$aRühlmann, Annika H.$$b0
000886070 245__ $$aUncoupling sodium channel dimers restores the phenotype of a pain‐linked Na v 1.7 channel mutation
000886070 260__ $$aMalden, MA$$bWiley$$c2020
000886070 3367_ $$2DRIVER$$aarticle
000886070 3367_ $$2DataCite$$aOutput Types/Journal article
000886070 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1613744876_5811
000886070 3367_ $$2BibTeX$$aARTICLE
000886070 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000886070 3367_ $$00$$2EndNote$$aJournal Article
000886070 520__ $$aBackground and PurposeThe voltage‐gated sodium channel Nav1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in humans. The hNav1.7/A1632E channel mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage‐gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is altered by the hNav1.7/A1632E mutation, and how dimerization modifies function of the pain‐linked mutation.Experimental ApproachWe applied atomistic molecular simulations to demonstrate the effect of the mutation on channel fast inactivation. Native PAGE was used to demonstrate channel dimerization, and electrophysiological measurements in HEK cells and Xenopus laevis oocytes were used to analyze the links between functional channel dimerization and impairment of fast inactivation by the hNav1.7/A1632E mutation.Key ResultsEnhanced persistent current through hNav1.7/A1632E channels was caused by impaired binding of the inactivation particle, which inhibits proper functioning of the recently proposed allosteric fast inactivation mechanism. hNav1.7 channels form dimers and the disease‐associated persistent current through hNav1.7/A1632E channels depends on their functional dimerization status: Expression of the synthetic peptide difopein, a 14‐3‐3 inhibitor known to functionally uncouple dimers, decreased hNav1.7/A1632E channel‐induced persistent currents.Conclusion and ImplicationsFunctional uncoupling of mutant hNav1.7/A1632E channel dimers restored their defective allosteric fast inactivation mechanism. Our findings support the concept of sodium channel dimerization and reveal its potential relevance for human pain syndromes.
000886070 536__ $$0G:(DE-HGF)POF3-551$$a551 - Functional Macromolecules and Complexes (POF3-551)$$cPOF3-551$$fPOF III$$x0
000886070 536__ $$0G:(DE-Juel1)jics42_20191101$$aMultiscale simulations of voltage-gated sodium channel complexes and clusters (jics42_20191101)$$cjics42_20191101$$fMultiscale simulations of voltage-gated sodium channel complexes and clusters$$x1
000886070 536__ $$0G:(DE-Juel1)jics40_20190501$$aMOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS (jics40_20190501)$$cjics40_20190501$$fMOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS$$x2
000886070 588__ $$aDataset connected to CrossRef
000886070 7001_ $$0P:(DE-HGF)0$$aKörner, Jannis$$b1
000886070 7001_ $$0P:(DE-HGF)0$$aHausmann, Ralf$$b2
000886070 7001_ $$0P:(DE-HGF)0$$aBebrivenski, Nikolay$$b3
000886070 7001_ $$0P:(DE-HGF)0$$aNeuhof, Christian$$b4
000886070 7001_ $$0P:(DE-HGF)0$$aDetro‐Dassen, Silvia$$b5
000886070 7001_ $$0P:(DE-HGF)0$$aHautvast, Petra$$b6
000886070 7001_ $$0P:(DE-HGF)0$$aBenasolo, Carène A.$$b7
000886070 7001_ $$00000-0001-9423-0453$$aMeents, Jannis$$b8
000886070 7001_ $$0P:(DE-Juel1)156429$$aMachtens, Jan-Philipp$$b9$$ufzj
000886070 7001_ $$0P:(DE-HGF)0$$aSchmalzing, Günther$$b10
000886070 7001_ $$00000-0001-6319-6272$$aLampert, Angelika$$b11$$eCorresponding author
000886070 773__ $$0PERI:(DE-600)2029728-2$$a10.1111/bph.15196$$gVol. 177, no. 19, p. 4481 - 4496$$n19$$p4481 - 4496$$tBritish journal of pharmacology$$v177$$x1476-5381$$y2020
000886070 8564_ $$uhttps://juser.fz-juelich.de/record/886070/files/bph.15196.pdf$$yOpenAccess
000886070 8564_ $$uhttps://juser.fz-juelich.de/record/886070/files/bph.15196.pdf?subformat=pdfa$$xpdfa$$yOpenAccess
000886070 909CO $$ooai:juser.fz-juelich.de:886070$$pdriver$$pVDB$$popen_access$$pdnbdelivery$$popenaire
000886070 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)156429$$aForschungszentrum Jülich$$b9$$kFZJ
000886070 9131_ $$0G:(DE-HGF)POF3-551$$1G:(DE-HGF)POF3-550$$2G:(DE-HGF)POF3-500$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bKey Technologies$$lBioSoft – Fundamentals for future Technologies in the fields of Soft Matter and Life Sciences$$vFunctional Macromolecules and Complexes$$x0
000886070 9132_ $$0G:(DE-HGF)POF4-899$$1G:(DE-HGF)POF4-890$$2G:(DE-HGF)POF4-800$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bProgrammungebundene Forschung$$lohne Programm$$vohne Topic$$x0
000886070 9141_ $$y2020
000886070 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bBRIT J PHARMACOL : 2018$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)3001$$2StatID$$aDEAL Wiley$$d2020-02-26$$wger
000886070 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0110$$2StatID$$aWoS$$bScience Citation Index$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0111$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess
000886070 915__ $$0LIC:(DE-HGF)CCBY4$$2HGFVOC$$aCreative Commons Attribution CC BY 4.0
000886070 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bBRIT J PHARMACOL : 2018$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0310$$2StatID$$aDBCoverage$$bNCBI Molecular Biology Database$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0320$$2StatID$$aDBCoverage$$bPubMed Central$$d2020-02-26
000886070 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2020-02-26
000886070 920__ $$lyes
000886070 9201_ $$0I:(DE-Juel1)IBI-1-20200312$$kIBI-1$$lMolekular- und Zellphysiologie$$x0
000886070 9201_ $$0I:(DE-82)080012_20140620$$kJARA-HPC$$lJARA - HPC$$x1
000886070 980__ $$ajournal
000886070 980__ $$aVDB
000886070 980__ $$aI:(DE-Juel1)IBI-1-20200312
000886070 980__ $$aI:(DE-82)080012_20140620
000886070 980__ $$aUNRESTRICTED
000886070 9801_ $$aFullTexts