Article abstract
Nature Neuroscience 11, 772 - 779 (2008)
Published online: 22 June 2008 | doi:10.1038/nn.2143
Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels
Diana M Bautista1,2,3,4, Yaron M Sigal1,2,4, Aaron D Milstein2, Jennifer L Garrison2,3, Julie A Zorn2, Pamela R Tsuruda1,2,3, Roger A Nicoll1,2 & David Julius1,2
Abstract
In traditional folk medicine, Xanthoxylum plants are referred to as 'toothache trees' because their anesthetic or counter-irritant properties render them useful in the treatment of pain. Psychophysical studies have identified hydroxy-
-sanshool as the compound most responsible for the unique tingling and buzzing sensations produced by Szechuan peppercorns or other Xanthoxylum preparations. Although it is generally agreed that sanshool elicits its effects by activating somatosensory neurons, the underlying cellular and molecular mechanisms remain a matter of debate. Here we show that hydroxy--sanshool excites two types of sensory neurons, including small-diameter unmyelinated cells that respond to capsaicin (but not mustard oil) as well as large-diameter myelinated neurons that express the neurotrophin receptor TrkC. We found that hydroxy--sanshool excites neurons through a unique mechanism involving inhibition of pH- and anesthetic-sensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18), providing a framework for understanding the unique and complex psychophysical sensations associated with the Szechuan pepper experience.
- Department of Physiology, University of California, San Francisco, 600 16th St., San Francisco, California 94143-2140, USA.
- Departments of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th St., San Francisco, California 94143-2140, USA.
- Present addresses: Department of Molecular and Cell Biology, University of California, Berkeley, 142 LSA, Berkeley, California, 94720-3200, USA (D.M.B.); The Rockefeller University, 230 York Ave., New York, New York 10065, USA (J.L.G.); Theravance, Inc., 901 Gateway Blvd., South San Francisco, California 94080, USA (P.R.S.).
- These authors contributed equally to this study.
Correspondence to: David Julius1,2 e-mail: julius@cmp.ucsf.edu
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