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Article: Molecular architecture of the voltage-dependent Na channel: Functional evidence for α helices in the pore

TitleMolecular architecture of the voltage-dependent Na channel: Functional evidence for α helices in the pore
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2001
PublisherRockefeller University Press. The Journal's web site is located at www.jgp.org/
Citation
Journal Of General Physiology, 2001, v. 118 n. 2, p. 171-181 How to Cite?
AbstractThe permeation pathway of the Na channel is formed by asymmetric loops (P segments) contributed by each of the four domains of the protein. In contrast to the analogous region of K channels, previously we (Yamagishi, T., M. Janecki, E. Marban, and G. Tomaselli. 1997. Biophys. J. 73:195-204) have shown that the P segments do not span the selectivity region, that is, they are accessible only from the extracellular surface. The portion of the P-segment NH 2-terminal to the selectivity region is referred to as SS1. To explore further the topology and functional role of the SS1 region, 40 amino acids NH 2-terminal to the selectivity ring (10 in each of the P segments) of the rat skeletal muscle Na channel were substituted by cysteine and expressed in tsA-201 cells. Selected mutants in each domain could be blocked with high affinity by externally applied Cd 2+ and were resistant to tetrodotoxin as compared with the wild-type channel. None of the externally applied sulfhydryl-specific methanethiosulfonate reagents modified the current through any of the mutant channels. Both R395C and R750C altered ionic selectivity, producing significant increases in K - and NH 4 + currents. The pattern of side chain accessibility is consistent with a pore helix like that observed in the crystal structure of the bacterial K channel, KcsA. Structure prediction of the Na channel using the program PHDhtm suggests an α helix in the SS1 region of each domain channel. We conclude that each of the P segments undergoes a hairpin turn in the permeation pathway, such that amino acids on both sides of the putative selectivity filter line the outer mouth of the pore. Evolutionary conservation of the pore helix motif from bacterial K channels to mammalian Na channels identifies this structure as a critical feature in the architecture of ion selective pores.
Persistent Identifierhttp://hdl.handle.net/10722/91470
ISSN
2015 Impact Factor: 4.511
2015 SCImago Journal Rankings: 3.061
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYamagishi, Ten_HK
dc.contributor.authorLi, RAen_HK
dc.contributor.authorHsu, Ken_HK
dc.contributor.authorMarbán, Een_HK
dc.contributor.authorTomaselli, GFen_HK
dc.date.accessioned2010-09-17T10:19:56Z-
dc.date.available2010-09-17T10:19:56Z-
dc.date.issued2001en_HK
dc.identifier.citationJournal Of General Physiology, 2001, v. 118 n. 2, p. 171-181en_HK
dc.identifier.issn0022-1295en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91470-
dc.description.abstractThe permeation pathway of the Na channel is formed by asymmetric loops (P segments) contributed by each of the four domains of the protein. In contrast to the analogous region of K channels, previously we (Yamagishi, T., M. Janecki, E. Marban, and G. Tomaselli. 1997. Biophys. J. 73:195-204) have shown that the P segments do not span the selectivity region, that is, they are accessible only from the extracellular surface. The portion of the P-segment NH 2-terminal to the selectivity region is referred to as SS1. To explore further the topology and functional role of the SS1 region, 40 amino acids NH 2-terminal to the selectivity ring (10 in each of the P segments) of the rat skeletal muscle Na channel were substituted by cysteine and expressed in tsA-201 cells. Selected mutants in each domain could be blocked with high affinity by externally applied Cd 2+ and were resistant to tetrodotoxin as compared with the wild-type channel. None of the externally applied sulfhydryl-specific methanethiosulfonate reagents modified the current through any of the mutant channels. Both R395C and R750C altered ionic selectivity, producing significant increases in K - and NH 4 + currents. The pattern of side chain accessibility is consistent with a pore helix like that observed in the crystal structure of the bacterial K channel, KcsA. Structure prediction of the Na channel using the program PHDhtm suggests an α helix in the SS1 region of each domain channel. We conclude that each of the P segments undergoes a hairpin turn in the permeation pathway, such that amino acids on both sides of the putative selectivity filter line the outer mouth of the pore. Evolutionary conservation of the pore helix motif from bacterial K channels to mammalian Na channels identifies this structure as a critical feature in the architecture of ion selective pores.en_HK
dc.languageengen_HK
dc.publisherRockefeller University Press. The Journal's web site is located at www.jgp.org/en_HK
dc.relation.ispartofJournal of General Physiologyen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAmino Acid Sequence - geneticsen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCadmium - pharmacologyen_HK
dc.subject.meshElectrophysiologyen_HK
dc.subject.meshForecastingen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMesylates - pharmacologyen_HK
dc.subject.meshModels, Molecularen_HK
dc.subject.meshMolecular Conformationen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshProtein Structure, Secondaryen_HK
dc.subject.meshRatsen_HK
dc.subject.meshSodium Channels - drug effects - genetics - physiologyen_HK
dc.subject.meshTetrodotoxin - pharmacologyen_HK
dc.titleMolecular architecture of the voltage-dependent Na channel: Functional evidence for α helices in the poreen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1085/jgp.118.2.171en_HK
dc.identifier.pmid11479344-
dc.identifier.scopuseid_2-s2.0-0034890072en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034890072&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume118en_HK
dc.identifier.issue2en_HK
dc.identifier.spage171en_HK
dc.identifier.epage181en_HK
dc.identifier.isiWOS:000170349800004-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYamagishi, T=55057431600en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridHsu, K=36779614100en_HK
dc.identifier.scopusauthoridMarbán, E=8075977300en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK

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