| Low concentrations of tetrodotoxin interact with tetrodotoxin-resistant voltage-gated sodium channels. | |
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MedLine Citation:
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PMID: 18552876 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Tetrodotoxin (TTX) is used to distinguish between two classes of voltage-gated sodium channel (VGSC)--TTX sensitive (TTXS) and TTX resistant (TTXR). The resistance of TTXR VGSCs is thought to result from a low binding affinity of TTX, although at high TTX concentrations channel block does occur. Here, we show that, at concentrations below those which produce block, TTX can bind to TTXR VGSCs. EXPERIMENTAL APPROACH: Whole-cell voltage clamp recordings were made from dissociated rat dorsal root ganglion neurones that expressed both TTXS and TTXR sodium currents. Voltage-gated calcium currents were blocked by 10 microM extracellular lanthanum chloride. TTXS, but not TTXR, current was suppressed by using a holding potential of -50 mV, and the effect of TTX on the isolated TTXR current was explored. KEY RESULTS: Extracellular application of 0.5 microM TTX produced a 40% increase in TTXR current amplitude, a negative shift in the voltage-dependence of current activation (approximately -8 mV) and inactivation (approximately -10 mV) and increased rates of current activation and inactivation. The effect of TTX on current amplitude was dose-dependent (EC50 = 364 nM). Removal of lanthanum prevented the effect of TTX on TTXR current amplitude, whereas reducing extracellular calcium did not. CONCLUSIONS AND IMPLICATIONS: The findings are consistent with an interpretation that TTX relieves a tonic block of the TTXR VGSC by lanthanum. We conclude that TTX binds to the TTXR VGSC at low concentrations, without blocking it. This appears to be the first demonstration of a clear distinction between binding affinity and blocking potency of a channel-blocking agent. |
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Authors:
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Ce Farmer; Kj Smith; Rj Docherty |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-06-16 |
Journal Detail:
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Title: British journal of pharmacology Volume: 155 ISSN: 0007-1188 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2008 Sep |
Date Detail:
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Created Date: 2008-08-26 Completed Date: 2008-12-18 Revised Date: 2010-08-16 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 34-43 Citation Subset: IM |
Affiliation:
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King's College London, Department of Clinical Neurosciences, London, UK. c.farmer@ion.ucl.ac.uk |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcium / metabolism Cells, Cultured Dose-Response Relationship, Drug Ganglia, Spinal / drug effects, metabolism Lanthanum / metabolism Membrane Potentials Nerve Tissue Proteins / drug effects Neurons / drug effects*, metabolism Neuropeptides / metabolism Rats Rats, Inbred Lew Rats, Sprague-Dawley Sodium Channel Blockers / metabolism, pharmacology* Sodium Channels / drug effects*, metabolism Tetrodotoxin / metabolism, pharmacology* Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Nerve Tissue Proteins; 0/Neuropeptides; 0/Scn11a protein, rat; 0/Sodium Channel Blockers; 0/Sodium Channels; 0/sensory neuron specific (SNS) sodium channel; 0/tetrodotoxin-binding protein; 4368-28-9/Tetrodotoxin; 7439-91-0/Lanthanum; 7440-70-2/Calcium |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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