Structural Determinants of Drugs Acting on the Nav1 .8 Channel.
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| Title: | Structural Determinants of Drugs Acting on the Na |
|---|---|
| Authors: | Browne, Liam E.1, Blaney, Frank E.2, Yusaf, Shahnaz P.3, CIare, Jeff J.4, Wray, Dennis1 d.wray@Ieeds.ac.uk |
| Source: | Journal of Biological Chemistry. 4/17/2009, Vol. 284 Issue 16, p10523-10536. 14p. 1 Chart, 1 Graph. |
| Subjects: | Ligands (Biochemistry), Alanine, Genetic mutation, Effect of drugs on cells, Drug activation |
| Abstract: | The aim of this work is to study the role of pore residues on drug binding in the Nav1.8 channel. Alanine mutations were made in the S6 segments, chosen on the basis of their roles in other Nav subtypes; whole cell patch clamp recordings were made from mammalian ND7/23 cells. Mutations of some residues caused shifts in voltage dependence of activation and inactivation, and gave faster time course of inactivation, indicating that the residues mutated play important roles in both activation and inactivation in the Nav1.8 channel. The resting and inactivated state affinities of tetracaine for the channel were reduced by mutations 1381A, F1710A, and Y1717A (for the latter only inactivated state affinity was measured), and by mutation F1710A for the Nav1.8-selective compound A-803467, showing the involvement of these residues for each compound, respectively. For both compounds, mutation L1410A caused the unexpected appearance of a complete resting block even at extremely low concentrations. Resting block of native channels by compound A-803467 could be partially removed ("disinhibition") by repetitive stimulation or by a test pulse after recovery from inactivation; the magnitude of the latter effect was increased for all the mutants studied. Tetracaine did not show this effect for native channels, but disinhibition was seen particularly for mutants L1410A and F1710A. The data suggest differing, but partially overlapping, areas of binding of A-803467 and tetracaine. Docking of the ligands into a three-dimensional model of the Nav1.8 channel gave interesting insight as to how the ligands may interact with pore residues. [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 39059809 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Structural Determinants of Drugs Acting on the Na<subscript>v</subscript>1 .8 Channel. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Browne%2C+Liam+E%2E%22">Browne, Liam E.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Blaney%2C+Frank+E%2E%22">Blaney, Frank E.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Yusaf%2C+Shahnaz+P%2E%22">Yusaf, Shahnaz P.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22CIare%2C+Jeff+J%2E%22">CIare, Jeff J.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Wray%2C+Dennis%22">Wray, Dennis</searchLink><relatesTo>1</relatesTo><i> d.wray@Ieeds.ac.uk</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 4/17/2009, Vol. 284 Issue 16, p10523-10536. 14p. 1 Chart, 1 Graph. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Ligands+%28Biochemistry%29%22">Ligands (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Alanine%22">Alanine</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+mutation%22">Genetic mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Effect+of+drugs+on+cells%22">Effect of drugs on cells</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+activation%22">Drug activation</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: The aim of this work is to study the role of pore residues on drug binding in the Nav1.8 channel. Alanine mutations were made in the S6 segments, chosen on the basis of their roles in other Nav subtypes; whole cell patch clamp recordings were made from mammalian ND7/23 cells. Mutations of some residues caused shifts in voltage dependence of activation and inactivation, and gave faster time course of inactivation, indicating that the residues mutated play important roles in both activation and inactivation in the Nav1.8 channel. The resting and inactivated state affinities of tetracaine for the channel were reduced by mutations 1381A, F1710A, and Y1717A (for the latter only inactivated state affinity was measured), and by mutation F1710A for the Nav1.8-selective compound A-803467, showing the involvement of these residues for each compound, respectively. For both compounds, mutation L1410A caused the unexpected appearance of a complete resting block even at extremely low concentrations. Resting block of native channels by compound A-803467 could be partially removed ("disinhibition") by repetitive stimulation or by a test pulse after recovery from inactivation; the magnitude of the latter effect was increased for all the mutants studied. Tetracaine did not show this effect for native channels, but disinhibition was seen particularly for mutants L1410A and F1710A. The data suggest differing, but partially overlapping, areas of binding of A-803467 and tetracaine. Docking of the ligands into a three-dimensional model of the Nav1.8 channel gave interesting insight as to how the ligands may interact with pore residues. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1074/jbc.M807569200 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 14 StartPage: 10523 Subjects: – SubjectFull: Ligands (Biochemistry) Type: general – SubjectFull: Alanine Type: general – SubjectFull: Genetic mutation Type: general – SubjectFull: Effect of drugs on cells Type: general – SubjectFull: Drug activation Type: general Titles: – TitleFull: Structural Determinants of Drugs Acting on the Nav1 .8 Channel. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Browne, Liam E. – PersonEntity: Name: NameFull: Blaney, Frank E. – PersonEntity: Name: NameFull: Yusaf, Shahnaz P. – PersonEntity: Name: NameFull: CIare, Jeff J. – PersonEntity: Name: NameFull: Wray, Dennis IsPartOfRelationships: – BibEntity: Dates: – D: 17 M: 04 Text: 4/17/2009 Type: published Y: 2009 Identifiers: – Type: issn-print Value: 00219258 Numbering: – Type: volume Value: 284 – Type: issue Value: 16 Titles: – TitleFull: Journal of Biological Chemistry Type: main |
| ResultId | 1 |
