Inhibition of TRPA1 by General Anesthetics.

Several general anesthetics (GAs) produce pain/irritation upon administration and this occurs predominantly through the activation of the nociceptive ion channel, Transient Receptor Potential Ankyrin Type 1 (TRPA1). However, the effects of GAs on agonist-mediated TRPA1 activity are unclear. Here we show that a diverse range of noxious and non-noxious volatile anesthetics, at clinically relevant concentrations, inhibit ligand-activated TRPA1 currents. These effects are species-specific; GAs blocks mammalian TRPA1 without affecting the Drosophila ortholog. Further, propofol inhibits rodent but not human TRPA1. Analysis of chimeric TRPA1 proteins and mutagenesis combined reveals two amino acid residues located in the S5 domain, Ser 873 and Thr 874, that are critical for the inhibitory effects of isoflurane and propofol. Introduction of these residues into dTRPA1 confers anesthetic inhibition. Further, several residues lining the presumptive binding pocket for noxious GAs, are not required for the inhibitory effects of GAs. We conclude that anesthetics inhibit TRPA1 by interacting at a site distinct from the activation site. The inhibitory effects of GAs at TRPA1 may contribute to the diverse pharmacological action of these drugs, including the regulation of pain signaling and vascular tone. SIGNIFICANCE STATEMENT: We show that both noxious and non-noxious general anesthetics inhibit agonist-evoked TRPA1 activity and identify critical amino acid residues located in the pore domain. Inhibition of TRPA1 may affect pain and vascular signaling during anesthesia.