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Stinging Sensations: Activation Mechanisms of the Wasabi Receptor, TRPA1

  • Author(s): Lin King, John V.
  • Advisor(s): Julius, David
  • et al.
Abstract

TRPA1 - also known as the ‘wasabi receptor’ - is activated by pungent natural products from mustard and allium plants and is responsible for the sinus clearing or eye stinging pain that one experiences when eating horse radish or chopping an onion. More importantly, TRPA1 is a receptor for an astoundingly broad class of volatile environmental irritants and endogenous pro-algesic agents that elicit or exacerbate tissue damage, pain, and neurogenic inflammation. Many of these irritants are chemically reactive electrophiles that activate TRPA1 through a fascinating mechanism involving covalent modification of the channel’s cytoplasmic N-terminus, a phenomenon that is not well understood at the biochemical or structural level. TRPA1 also functions as a ‘receptor-operated’ channel that is activated downstream of phospholipase C signaling pathways, such as those involved in the transduction of pruritic signals. Together, these actions make TRPA1 a major contributor to a broad range of chemo-nociceptive actions include pain and itch.

In this work we have exploited natural product pharmacology, functional recording, and structural methods to understand how TRPA1 is activated by a range of stimuli (reactive and non-reactive, direct and indirect). Collectively, these data draw a detailed mechanistic picture of how this important chemo-nociceptive ion channel detects physiological stimuli, transduces this information into neuronal excitation, and is regulated by cellular events. In light of TRPA1’s well recognized role in acute and persistent pain and itch, our findings are of both investigational and therapeutic import. Beyond TRPA1, they are of general relevance to illuminating the gating mechanisms other sensory TRP channels, several of which are also regulated downstream of metabotropic receptors and/or by cellular calcium.

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