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Activation of TRPA1 by membrane permeable local anesthetics.
Mol Pain. 2011 Aug 23; 7:62.MP

Abstract

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)P₂-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.

Authors+Show Affiliations

Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21861907

Citation

Leffler, Andreas, et al. "Activation of TRPA1 By Membrane Permeable Local Anesthetics." Molecular Pain, vol. 7, 2011, p. 62.
Leffler A, Lattrell A, Kronewald S, et al. Activation of TRPA1 by membrane permeable local anesthetics. Mol Pain. 2011;7:62.
Leffler, A., Lattrell, A., Kronewald, S., Niedermirtl, F., & Nau, C. (2011). Activation of TRPA1 by membrane permeable local anesthetics. Molecular Pain, 7, 62. https://doi.org/10.1186/1744-8069-7-62
Leffler A, et al. Activation of TRPA1 By Membrane Permeable Local Anesthetics. Mol Pain. 2011 Aug 23;7:62. PubMed PMID: 21861907.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of TRPA1 by membrane permeable local anesthetics. AU - Leffler,Andreas, AU - Lattrell,Anja, AU - Kronewald,Sergej, AU - Niedermirtl,Florian, AU - Nau,Carla, Y1 - 2011/08/23/ PY - 2011/01/18/received PY - 2011/08/23/accepted PY - 2011/8/25/entrez PY - 2011/8/25/pubmed PY - 2011/12/13/medline SP - 62 EP - 62 JF - Molecular pain JO - Mol Pain VL - 7 N2 - 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)P₂-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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/21861907/Activation_of_TRPA1_by_membrane_permeable_local_anesthetics_ L2 - https://journals.sagepub.com/doi/10.1186/1744-8069-7-62?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -