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Molecular determinants of species-specific activation or blockade of TRPA1 channels.
J Neurosci. 2008 May 07; 28(19):5063-71.JN

Abstract

TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal). However, how covalent modification leads to channel opening is not understood. Here, we report that electrophilic, thioaminal-containing compounds [e.g., CMP1 (4-methyl-N-[2,2,2-trichloro-1-(4-nitro-phenylsulfanyl)-ethyl]-benzamide)] covalently modify cysteine residues but produce striking species-specific effects [i.e., activation of rat TRPA1 (rTRPA1) and blockade of human TRPA1 (hTRPA1) activation by reactive and nonreactive agonists]. Through characterizing rTRPA1 and hTRPA1 chimeric channels and point mutations, we identified several residues in the upper portion of the S6 transmembrane domains as critical determinants of the opposite channel gating: Ala-946 and Met-949 of rTRPA1 determine channel activation, whereas equivalent residues of hTRPA1 (Ser-943 and Ile-946) determine channel block. Furthermore, side-chain replacements at these critical residues profoundly affect channel function. Therefore, our findings reveal a molecular basis of species-specific channel gating and provide novel insights into how TRPA1 respond to stimuli.

Authors+Show Affiliations

Neuroscience, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6125, USA. jun.x.chen@abbott.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18463259

Citation

Chen, Jun, et al. "Molecular Determinants of Species-specific Activation or Blockade of TRPA1 Channels." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 28, no. 19, 2008, pp. 5063-71.
Chen J, Zhang XF, Kort ME, et al. Molecular determinants of species-specific activation or blockade of TRPA1 channels. J Neurosci. 2008;28(19):5063-71.
Chen, J., Zhang, X. F., Kort, M. E., Huth, J. R., Sun, C., Miesbauer, L. J., Cassar, S. C., Neelands, T., Scott, V. E., Moreland, R. B., Reilly, R. M., Hajduk, P. J., Kym, P. R., Hutchins, C. W., & Faltynek, C. R. (2008). Molecular determinants of species-specific activation or blockade of TRPA1 channels. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 28(19), 5063-71. https://doi.org/10.1523/JNEUROSCI.0047-08.2008
Chen J, et al. Molecular Determinants of Species-specific Activation or Blockade of TRPA1 Channels. J Neurosci. 2008 May 7;28(19):5063-71. PubMed PMID: 18463259.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular determinants of species-specific activation or blockade of TRPA1 channels. AU - Chen,Jun, AU - Zhang,Xu-Feng, AU - Kort,Michael E, AU - Huth,Jeffrey R, AU - Sun,Chaohong, AU - Miesbauer,Laura J, AU - Cassar,Steven C, AU - Neelands,Torben, AU - Scott,Victoria E, AU - Moreland,Robert B, AU - Reilly,Regina M, AU - Hajduk,Philip J, AU - Kym,Philip R, AU - Hutchins,Charles W, AU - Faltynek,Connie R, PY - 2008/5/9/pubmed PY - 2008/6/14/medline PY - 2008/5/9/entrez SP - 5063 EP - 71 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 28 IS - 19 N2 - TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal). However, how covalent modification leads to channel opening is not understood. Here, we report that electrophilic, thioaminal-containing compounds [e.g., CMP1 (4-methyl-N-[2,2,2-trichloro-1-(4-nitro-phenylsulfanyl)-ethyl]-benzamide)] covalently modify cysteine residues but produce striking species-specific effects [i.e., activation of rat TRPA1 (rTRPA1) and blockade of human TRPA1 (hTRPA1) activation by reactive and nonreactive agonists]. Through characterizing rTRPA1 and hTRPA1 chimeric channels and point mutations, we identified several residues in the upper portion of the S6 transmembrane domains as critical determinants of the opposite channel gating: Ala-946 and Met-949 of rTRPA1 determine channel activation, whereas equivalent residues of hTRPA1 (Ser-943 and Ile-946) determine channel block. Furthermore, side-chain replacements at these critical residues profoundly affect channel function. Therefore, our findings reveal a molecular basis of species-specific channel gating and provide novel insights into how TRPA1 respond to stimuli. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/18463259/Molecular_determinants_of_species_specific_activation_or_blockade_of_TRPA1_channels_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=18463259 DB - PRIME DP - Unbound Medicine ER -