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The Journal of Neuroscience, June 13, 2007, 27(24):6500-6509; doi:10.1523/JNEUROSCI.0623-07.2007

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Cellular/Molecular
Requirement of a Soluble Intracellular Factor for Activation of Transient Receptor Potential A1 by Pungent Chemicals: Role of Inorganic Polyphosphates

Donghee Kim and Eric J. Cavanaugh

Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, Illinois 60064

Correspondence should be addressed to Dr. Donghee Kim, Department of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064. Email: donghee.kim{at}rosalindfranklin.edu

Pungent chemicals such as allyl isothiocyanate (AITC), cinnamaldehyde, and allicin, produce nociceptive sensation by directly activating transient receptor potential A1 (TRPA1) expressed in sensory afferent neurons. In this study, we found that pungent chemicals added to the pipette or bath solution easily activated TRPA1 in cell-attached patches but failed to do so in inside-out or outside-out patches. Thus, a soluble cytosolic factor was required to activate TRPA1. N-Ethylmaleimide, (2-aminoethyl)-methane thiosulfonate, 2-aminoethoxydiphneyl borate, and trinitrophenol, compounds that are known to activate TRPA1, also failed to activate it in inside-out patches. To identify a factor that supports activation of TRPA1 by pungent chemicals, we screened 30 intracellular molecules known to modulate ion channels. Among them, pyrophosphate (PPi) and polytriphosphate (PPPi) were found to support activation of TRPA1 by pungent chemicals. Structure–function studies showed that inorganic polyphosphates (polyP_n, where n = number of phosphates) with at least four phosphate groups were highly effective (polyP4 polyP65 polyP45 polyP25 > PPPi > PPi), with K_1/2 values ranging from 0.2 to 2.8 mM. Inositol-trisphosphate and inositol-hexaphosphate also partially supported activation of TRPA1 by AITC. ATP, GTP, and phosphatidylinositol-4,5-bisphosphate that have three phosphate groups did not support TRPA1 activation. TRPA1 recorded from cell bodies of trigeminal ganglion neurons showed similar behavior with respect to sensitivity to pungent chemicals; no activation was observed in inside-out patches unless a polyphosphate was present. These results show that TRPA1 requires an intracellular factor to adopt a functional conformation that is sensitive to pungent chemicals and suggest that polyphosphates may partly act as such a factor.

Key words: channel; chemosensory; intracellular signaling; neuron; pain; patch clamp

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Received Feb. 12, 2007; revised May 10, 2007; accepted May 11, 2007.

Correspondence should be addressed to Dr. Donghee Kim, Department of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064. Email: donghee.kim{at}rosalindfranklin.edu

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