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High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain
Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, s...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885214/ https://www.ncbi.nlm.nih.gov/pubmed/17565368 http://dx.doi.org/10.1371/journal.pone.0000515 |
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author | Drew, Liam J. Rugiero, Francois Cesare, Paolo Gale, Jonathan E. Abrahamsen, Bjarke Bowden, Sarah Heinzmann, Sebastian Robinson, Michelle Brust, Andreas Colless, Barbara Lewis, Richard J. Wood, John N. |
author_facet | Drew, Liam J. Rugiero, Francois Cesare, Paolo Gale, Jonathan E. Abrahamsen, Bjarke Bowden, Sarah Heinzmann, Sebastian Robinson, Michelle Brust, Andreas Colless, Barbara Lewis, Richard J. Wood, John N. |
author_sort | Drew, Liam J. |
collection | PubMed |
description | Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC(50) 1 µM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain. |
format | Text |
id | pubmed-1885214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-18852142007-06-13 High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain Drew, Liam J. Rugiero, Francois Cesare, Paolo Gale, Jonathan E. Abrahamsen, Bjarke Bowden, Sarah Heinzmann, Sebastian Robinson, Michelle Brust, Andreas Colless, Barbara Lewis, Richard J. Wood, John N. PLoS One Research Article Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC(50) 1 µM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain. Public Library of Science 2007-06-13 /pmc/articles/PMC1885214/ /pubmed/17565368 http://dx.doi.org/10.1371/journal.pone.0000515 Text en Drew et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Drew, Liam J. Rugiero, Francois Cesare, Paolo Gale, Jonathan E. Abrahamsen, Bjarke Bowden, Sarah Heinzmann, Sebastian Robinson, Michelle Brust, Andreas Colless, Barbara Lewis, Richard J. Wood, John N. High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain |
title | High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain |
title_full | High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain |
title_fullStr | High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain |
title_full_unstemmed | High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain |
title_short | High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain |
title_sort | high-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885214/ https://www.ncbi.nlm.nih.gov/pubmed/17565368 http://dx.doi.org/10.1371/journal.pone.0000515 |
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