Isopentenyl pyrophosphate is a novel antinociceptive substance that inhibits TRPV3 and TRPA1 ion channels

Sangsu Bang, Sungjae Yoo, Tae Jin Yang, Hawon Cho, Sun Wook Hwang

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Transient receptor potential ion channels (TRPs) expressed in the periphery sense and electrically transduce noxious stimuli to transmit the signals to the brain. Many natural and synthetic ligands for the sensory TRPs have been found, but little is known about endogenous inhibitors of these TRP channels. Recently, we reported that farnesyl pyrophosphate, an endogenous substance produced in the mevalonate pathway, is a specific activator for TRPV3. Here, we show that isopentenyl pyrophosphate (IPP), an upstream metabolite in the same pathway, is a dual inhibitor for TRPA1 and TRPV3. By using Ca2+ imaging and voltage clamp experiments with human embryo kidney cell heterologous expression system, cultured sensory neurons, and epidermal keratinocytes, we demonstrate that micromolar IPP suppressed responses to specific agonists of TRPA1 and TRPV3. Consistently, peripheral IPP administration attenuated TRPA1 and TRPV3 agonist-specific acute pain behaviors. Furthermore, local IPP pretreatment significantly reversed mechanical and thermal hypersensitivity of inflamed animals. Taken together, the present study suggests that IPP is a novel endogenous TRPA1 and TRPV3 inhibitor that causes local antinociception. Our results may provide useful chemical information to elucidate TRP physiology in peripheral pain sensation. Isopentenyl pyrophosphate, a substance generated in the mevalonate metabolism, inhibits TRPA1 and TRPV3, and it results in peripheral antinociception in a receptor-dependent manner.

Original languageEnglish
Pages (from-to)1156-1164
Number of pages9
JournalPain
Volume152
Issue number5
DOIs
Publication statusPublished - 2011 May 1

Keywords

  • Antinociception
  • Isopentenyl pyrophosphate
  • Keratinocyte
  • Pain
  • Sensory neuron
  • TRPA1
  • TRPV3

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology

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