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NPPB structure-specifically activates TRPA1 channels.
Biochem Pharmacol. 2010 Jul 01; 80(1):113-21.BP

Abstract

TRPA1 channels have been found to play an important role in mammalian pain sensation, especially when the pain is caused by chemicals on site of inflammation. A large number of structurally diverse chemicals are found to activate TRPA1 channels, implicating a potential chemosensor in neuronal nociception. Identification of the channel activation by cysteine modification through covalent chemical reaction provides arguments for the diversity of the agonist structures. However, it is largely unknown how nonreactive compounds activate TRPA1 channels. Here, we report that NPPB, a classic Cl(-) channel blocker, potently activated human TRPA1 channels overexpressed in mammalian HEK-293 cells. This effect was confirmed in Ca(2+) imaging assay, patch clamp whole cell and single channel recordings. The NPPB response was quick, fully reversible and replicable, contrary to the effect of covalent modification by AITC. The mutagenesis studies revealed a refreshed look at several mutations known to be critical for the actions of AITC and menthol. The blocking profile of NPPB on these mutants showed that the NPPB activation was similar to that of FTS and different from AITC and menthol. The results indicated a possible close interaction between S5 and N-terminal domains of the channel. We also tested a group of NPPB analogs on TRPA1 channel activities. The results demonstrated that NPPB activation was tightly associated with chemical structure. None of the single chemical group was sufficient to activate the channel, indicating that NPPB activated TRPA1 through a structure-specific mechanism.

Authors+Show Affiliations

Department of Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. liuk2277@yahoo.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20226176

Citation

Liu, Kun, et al. "NPPB Structure-specifically Activates TRPA1 Channels." Biochemical Pharmacology, vol. 80, no. 1, 2010, pp. 113-21.
Liu K, Samuel M, Ho M, et al. NPPB structure-specifically activates TRPA1 channels. Biochem Pharmacol. 2010;80(1):113-21.
Liu, K., Samuel, M., Ho, M., Harrison, R. K., & Paslay, J. W. (2010). NPPB structure-specifically activates TRPA1 channels. Biochemical Pharmacology, 80(1), 113-21. https://doi.org/10.1016/j.bcp.2010.03.005
Liu K, et al. NPPB Structure-specifically Activates TRPA1 Channels. Biochem Pharmacol. 2010 Jul 1;80(1):113-21. PubMed PMID: 20226176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NPPB structure-specifically activates TRPA1 channels. AU - Liu,Kun, AU - Samuel,Manoj, AU - Ho,Melisa, AU - Harrison,Richard K, AU - Paslay,Jeff W, Y1 - 2010/03/10/ PY - 2010/01/26/received PY - 2010/03/02/revised PY - 2010/03/03/accepted PY - 2010/3/16/entrez PY - 2010/3/17/pubmed PY - 2010/5/21/medline SP - 113 EP - 21 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 80 IS - 1 N2 - TRPA1 channels have been found to play an important role in mammalian pain sensation, especially when the pain is caused by chemicals on site of inflammation. A large number of structurally diverse chemicals are found to activate TRPA1 channels, implicating a potential chemosensor in neuronal nociception. Identification of the channel activation by cysteine modification through covalent chemical reaction provides arguments for the diversity of the agonist structures. However, it is largely unknown how nonreactive compounds activate TRPA1 channels. Here, we report that NPPB, a classic Cl(-) channel blocker, potently activated human TRPA1 channels overexpressed in mammalian HEK-293 cells. This effect was confirmed in Ca(2+) imaging assay, patch clamp whole cell and single channel recordings. The NPPB response was quick, fully reversible and replicable, contrary to the effect of covalent modification by AITC. The mutagenesis studies revealed a refreshed look at several mutations known to be critical for the actions of AITC and menthol. The blocking profile of NPPB on these mutants showed that the NPPB activation was similar to that of FTS and different from AITC and menthol. The results indicated a possible close interaction between S5 and N-terminal domains of the channel. We also tested a group of NPPB analogs on TRPA1 channel activities. The results demonstrated that NPPB activation was tightly associated with chemical structure. None of the single chemical group was sufficient to activate the channel, indicating that NPPB activated TRPA1 through a structure-specific mechanism. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/20226176/NPPB_structure_specifically_activates_TRPA1_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(10)00170-X DB - PRIME DP - Unbound Medicine ER -