Several general anesthetics (GAs) produce pain or 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 rodent TRPA1 without affecting the Drosophila ortholog. Furthermore, 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, Ser876 and Thr877, that are critical for the inhibitory effects of isoflurane and propofol. Introduction of these residues into Drosophila TRPA1 confers anesthetic inhibition. Furthermore, 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.

中文翻译：

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全身麻醉剂对配体门控 TRPA1 的抑制。

几种全身麻醉剂 (GA) 在给药时会产生疼痛或刺激，这主要是通过激活伤害性离子通道、瞬时受体电位锚蛋白 1 (TRPA1) 来发生的。然而，GAs 对激动剂介导的 TRPA1 活性的影响尚不清楚。在这里，我们展示了各种具有临床相关浓度的有毒和无毒挥发性麻醉剂，可抑制配体激活的 TRPA1 电流。这些影响是物种特异性的；GAs 阻断啮齿动物 TRPA1 而不影响果蝇直系同源。此外，丙泊酚抑制啮齿动物，但不抑制人类 TRPA1。嵌合 TRPA1 蛋白分析和诱变相结合，揭示了位于 S5 域的两个氨基酸残基 Ser876 和 Thr877，它们对异氟醚和丙泊酚的抑制作用至关重要。将这些残基引入果蝇TRPA1 会产生麻醉抑制。此外，GAs 的抑制作用不需要位于有毒 GAs 的假定结合口袋内的几个残基。我们得出结论，麻醉剂通过在不同于激活位点的位点相互作用来抑制 TRPA1。GAs 对 TRPA1 的抑制作用可能有助于这些药物的多种药理作用。