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Activation of TRPA1 by membrane permeable local anesthetics

BACKGROUND: Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na(+ )channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the caps...

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Autores principales: Leffler, Andreas, Lattrell, Anja, Kronewald, Sergej, Niedermirtl, Florian, Nau, Carla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179737/
https://www.ncbi.nlm.nih.gov/pubmed/21861907
http://dx.doi.org/10.1186/1744-8069-7-62
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author Leffler, Andreas
Lattrell, Anja
Kronewald, Sergej
Niedermirtl, Florian
Nau, Carla
author_facet Leffler, Andreas
Lattrell, Anja
Kronewald, Sergej
Niedermirtl, Florian
Nau, Carla
author_sort Leffler, Andreas
collection PubMed
description BACKGROUND: Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na(+ )channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P(2)-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1. RESULTS: Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs. CONCLUSIONS: The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.
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spelling pubmed-31797372011-09-25 Activation of TRPA1 by membrane permeable local anesthetics Leffler, Andreas Lattrell, Anja Kronewald, Sergej Niedermirtl, Florian Nau, Carla Mol Pain Research BACKGROUND: Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na(+ )channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P(2)-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1. RESULTS: Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs. CONCLUSIONS: The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs. BioMed Central 2011-08-23 /pmc/articles/PMC3179737/ /pubmed/21861907 http://dx.doi.org/10.1186/1744-8069-7-62 Text en Copyright ©2011 Leffler et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Leffler, Andreas
Lattrell, Anja
Kronewald, Sergej
Niedermirtl, Florian
Nau, Carla
Activation of TRPA1 by membrane permeable local anesthetics
title Activation of TRPA1 by membrane permeable local anesthetics
title_full Activation of TRPA1 by membrane permeable local anesthetics
title_fullStr Activation of TRPA1 by membrane permeable local anesthetics
title_full_unstemmed Activation of TRPA1 by membrane permeable local anesthetics
title_short Activation of TRPA1 by membrane permeable local anesthetics
title_sort activation of trpa1 by membrane permeable local anesthetics
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179737/
https://www.ncbi.nlm.nih.gov/pubmed/21861907
http://dx.doi.org/10.1186/1744-8069-7-62
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