Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels.
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-alpha-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-alpha-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-alpha-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.
Bautista
Diana M
DM
Department of Physiology, University of California, San Francisco, 600 16th St., San Francisco, California 94143-2140, USA.
Sigal
Yaron M
YM
Milstein
Aaron D
AD
Garrison
Jennifer L
JL
Zorn
Julie A
JA
Tsuruda
Pamela R
PR
Nicoll
Roger A
RA
Julius
David
D
D000577:Amides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D004558:Electric Stimulation / Q000379:methods; D017950:Ganglia, Sensory / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016900:Neurofilament Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D029222:Piper nigrum / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D020812:Receptor, trkC / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000172:deficiency; D050051:Transient Receptor Potential Channels / Q000172:deficiency
D000577:Amides; D016900:Neurofilament Proteins; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C051774:neurofilament protein H; C100574:sanshool; D011189:Potassium Chloride; D020812:Receptor, trkC; D002211:Capsaicin