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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Wray, Dennis Browne, Liam E. Blaney, Frank E. Yusaf, Shahnaz P. Clare, Jeff J. |
| Description | Author Affiliation: Browne LE ( Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.) |
| Abstract | The aim of this work is to study the role of pore residues on drug binding in the Na(V)1.8 channel. Alanine mutations were made in the S6 segments, chosen on the basis of their roles in other Na(V) 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 Na(V)1.8 channel. The resting and inactivated state affinities of tetracaine for the channel were reduced by mutations I381A, F1710A, and Y1717A (for the latter only inactivated state affinity was measured), and by mutation F1710A for the Na(V)1.8-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 Na(V)1.8 channel gave interesting insight as to how the ligands may interact with pore residues. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 16 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-04-17 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Aniline Compounds Chemistry Furans Molecular Structure Sodium Channel Blockers Sodium Channels Metabolism Amino Acid Sequence Anesthetics, Local Animals Binding Sites Ion Channel Gating Physiology Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed NAV1.8 Voltage-Gated Sodium Channel Patch-Clamp Techniques Protein Structure, Tertiary Sequence Alignment Genetics Tetracaine Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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