Neuroscience How Sanshool Produces One Singular Sensation

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Szechuan peppers, which are unrelated to black peppers or chili peppers, are harvested from various species of Xanthoxylum, a genus of plants traditionally known as "toothache trees" because of the characteristic tingling, numbing sensation they elicit. Using live-cell calcium imaging, Bautista et al. found that hydroxy--sanshool (sanshool, the active ingredient) purified from Szechuan pepper excited two main classes of cultured mouse sensory neurons. These comprised a subset of small-diameter unmyelinated neurons that expressed the capsaicin receptor TRPV1 and a subset of large-diameter myelinated neurons that expressed the neurotrophin receptor TrkC and were sensitive to osmotic stimuli. Whole-cell voltage-clamp analysis indicated that sanshool inhibited a background K⁺ leak current; sensitivity to pH and pharmacology implicated the KCNK family of two-pore K⁺ channels as sanshool targets. When different KCNK subtypes were expressed in Xenopus oocytes, only KCNK3, KCNK9, and KCNK18 were inhibited by sanshool; the effects of sanshool were reversible, independent of pH, and apparent on channels in excised membrane patches. In contrast, various excitatory channels, including TRPV1 and TRPA1 (which responds to mustard oil), did not appear to be sanshool targets. Cultured cerebellar granule neurons also showed calcium responses to sanshool; their sensitivity correlated with a temporal increase in expression of transcripts encoding KCNK3 and KCNK9, whereas KCNK18 appeared to play a key role in the sanshool sensitivity of cultured trigeminal ganglion sensory neurons. Thus, the unique sensation elicited by sanshool--described by the authors as "akin to...touching one’s tongue to the terminals of a 9-V battery"--appears to depend on an equally unusual mechanism of sensory neuron activation.

D. M. Bautista, Y. M. Sigal, A. D. Milstein, J. L. Garrison, J. A. Zorn, P. R. Tsuruda, R. A. Nicoll, D. Julius, Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat. Neurosci.11, 772-779 (2008). [PubMed]