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Why the Taste of Some Spicy Foods Lingers

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Science's STKE  06 Feb 2007:
Vol. 2007, Issue 372, pp. tw44
DOI: 10.1126/stke.3722007tw44

TRPA1 is a member of the transient receptor potential (TRP) family of ion channels and is involved in the sensation of noxious stimuli, including chemicals in food that are perceived as pungent or spicy. Macpherson et al. report that structurally diverse chemicals that can covalently interact with cysteine residues activate mouse TRPA1 channels. Using alkyne-modified agonists, they detected the alkyne-tagged residues on the channels using a fluorophore that reacted with the alkyne. Preincubation of the channel with cysteine-modifying agonists lacking the alkyne tag decreased the fluorescent signal (prevented access to the cysteines for the alkyne-tagged agonist). However, agonists, such as icilin, that cannot modify cysteines did not alter the labeling of the TRPA1 by the alkyne-tagged cysteine-modifying agonist. Thus, there is more than one way to activate TRPA1. Mass spectrometry analysis showed that 14 cysteines in the N-terminal cytosolic region were sites of modification. However, only three cysteines (Cys415, Cys422, Cys622) appeared to have an effect on channel activity based on mutagenesis analysis. Although mutation of any of these three cysteines reduced channel activity, normalized current analysis showed that channels with any of these mutations were selectively defective in response to cysteine-reactive agonists and not to icilin, with Cys622 showing the strongest decrease in responsiveness. The persistent stimulation predicted to occur in response to a covalent modification was validated by experiments in which an increase in calcium concentrations or single-channel activity was observed following washout of cysteine-modifying agonists. Caterina discusses this work and that of Hinman et al., who previously reported this mechanism of action.

L. J. Macpherson, A. E. Dubin, M. J. Evans, F. Marr, P. G. Schultz, B. F. Cravatt, A. Patapoutian, Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445, 541-545 (2007). [PubMed]

M. J. Caterina, Sticky spices. Nature 445, 491-492 (2007). [PubMed]

A. Hinman, H.-h. Chuang, D. M. Bautista, D. Julius, TRP channel activation by reversible covalent modification. Proc. Natl. Acad. Sci. U.S.A. 103, 19564-19568 (2006). [Abstract] [Full Text]

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