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Article: A multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptor

TitleA multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptor
Authors
Issue Date2005
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 2005, v. 67 n. 2, p. 424-434 How to Cite?
AbstractVoltage-gated Na+ (Nav) channels are responsible for initiating action potentials in excitable cells and are the targets of local anesthetics (LA). The LA receptor is localized to the cytoplasmic pore mouth formed by the S6 segments from all four domains (DI-DIV) but several outer pore-lining residues have also been shown to influence LA block (albeit somewhat modestly). Many of the reported amino acid substitutions, however, also disrupt the inactivated conformations that favor LA binding, complicating the interpretation of their specific effects on drug block. In this article, we report that an externally accessible aromatic residue in the Nav channel pore, DIV-Trp1531, when substituted with cysteine, completely abolished LA block (e.g., 300 μM mexiletine induced a use-dependent block with 65.0 ± 2.9% remaining current and -11.0 ± 0.6 mV of steady-state inactivation shift of wild-type (WT) channels versus 97.4 ± 0.7% and -2.4 ± 2.1 mV of W1531C, respectively; p < 0.05) without destabilizing fast inactivation (complete inactivation at 20 ms at -20 mV; V1/2 = -70.0 ± 1.6 mV versus -48.6 ± 0.5 mV of WT). W1531C also abolished internal QX-222 block (200 μM; 98.4 ± 3.4% versus 54.0 ± 3.2% of WT) without altering drug access. It is interesting that W1531Y restored WT blocking behavior, whereas W1531A channels exhibited an intermediate phenotype. Together, our results provide novel insights into the mechanism of drug action, and the structural relationship between the LA receptor and the outer pore vestibule.
Persistent Identifierhttp://hdl.handle.net/10722/124974
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSuk, YTen_HK
dc.contributor.authorTsushima, RGen_HK
dc.contributor.authorTomaselli, GFen_HK
dc.contributor.authorLi, RAen_HK
dc.contributor.authorBackx, PHen_HK
dc.date.accessioned2010-10-31T11:04:29Z-
dc.date.available2010-10-31T11:04:29Z-
dc.date.issued2005en_HK
dc.identifier.citationMolecular Pharmacology, 2005, v. 67 n. 2, p. 424-434en_HK
dc.identifier.issn0026-895Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/124974-
dc.description.abstractVoltage-gated Na+ (Nav) channels are responsible for initiating action potentials in excitable cells and are the targets of local anesthetics (LA). The LA receptor is localized to the cytoplasmic pore mouth formed by the S6 segments from all four domains (DI-DIV) but several outer pore-lining residues have also been shown to influence LA block (albeit somewhat modestly). Many of the reported amino acid substitutions, however, also disrupt the inactivated conformations that favor LA binding, complicating the interpretation of their specific effects on drug block. In this article, we report that an externally accessible aromatic residue in the Nav channel pore, DIV-Trp1531, when substituted with cysteine, completely abolished LA block (e.g., 300 μM mexiletine induced a use-dependent block with 65.0 ± 2.9% remaining current and -11.0 ± 0.6 mV of steady-state inactivation shift of wild-type (WT) channels versus 97.4 ± 0.7% and -2.4 ± 2.1 mV of W1531C, respectively; p < 0.05) without destabilizing fast inactivation (complete inactivation at 20 ms at -20 mV; V1/2 = -70.0 ± 1.6 mV versus -48.6 ± 0.5 mV of WT). W1531C also abolished internal QX-222 block (200 μM; 98.4 ± 3.4% versus 54.0 ± 3.2% of WT) without altering drug access. It is interesting that W1531Y restored WT blocking behavior, whereas W1531A channels exhibited an intermediate phenotype. Together, our results provide novel insights into the mechanism of drug action, and the structural relationship between the LA receptor and the outer pore vestibule.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_HK
dc.relation.ispartofMolecular Pharmacologyen_HK
dc.subject.meshAmino Acid Substitution - drug effects-
dc.subject.meshAmino Acids, Aromatic - antagonists and inhibitors - physiology-
dc.subject.meshAnesthetics, Local - metabolism-
dc.subject.meshReceptors, Drug - physiology-
dc.subject.meshSodium Channels - chemistry - genetics - physiology-
dc.titleA multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptoren_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0026-895X&volume=67&issue=2&spage=424&epage=434&date=2005&atitle=A+multi-functional+aromatic+residue+in+the+external+pore+vestibule+of+Na++Channels+contributes+to+the+local+anesthetic+receptor-
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1124/mol.67.2.en_HK
dc.identifier.pmid15659774-
dc.identifier.scopuseid_2-s2.0-13444269678en_HK
dc.identifier.hkuros183068en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-13444269678&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume67en_HK
dc.identifier.issue2en_HK
dc.identifier.spage424en_HK
dc.identifier.epage434en_HK
dc.identifier.isiWOS:000226412900010-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSuk, YT=6603542706en_HK
dc.identifier.scopusauthoridTsushima, RG=7006183117en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridBackx, PH=7006796226en_HK

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