Keshavaprasad Bharat, Liu Canhui, Au John D, Kindler Christoph H, Cotten Joseph F, Yost C Spencer
*Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California; Department of Anesthesia, University Hospital Basel, Basel, Switzerland.
Anesth Analg. 2005 Oct;101(4):1042-1049. doi: 10.1213/01.ane.0000168447.87557.5a.
TRESK (TWIK-related spinal cord K+ channel) is the most recently characterized member of the tandem-pore domain potassium channel (K2P) family. Human TRESK is potently activated by halothane, isoflurane, sevoflurane, and desflurane, making it the most sensitive volatile anesthetic-activated K2P channel yet described. Herein, we compare the anesthetic sensitivity and pharmacologic modulation of rodent versions of TRESK to their human orthologue. Currents passed by mouse and rat TRESK were enhanced by isoflurane at clinical concentrations but with significantly lower efficacy than human TRESK. Unlike human TRESK, the rodent TRESKs are strongly inhibited by acidic extracellular pH in the physiologic range. Zinc inhibited currents passed by both rodent TRESK in the low micromolar range but was without effect on human TRESK. Enantiomers of isoflurane that have stereoselective anesthetic potency in vivo produced stereospecific enhancement of the rodent TRESKs in vitro. Amide local anesthetics inhibited the rodent TRESKs at almost 10-fold smaller concentrations than that which inhibit human TRESK. These results identified interspecies differences and similarities in the pharmacology of TRESK. Further characterization of TRESK expression patterns is needed to understand their role in anesthetic mechanisms.
Mouse and rat TRESK (TWIK-related spinal cord K+ channel) have different pharmacologic responses compared with human TRESK. In particular, we found stereospecific differences in response to isoflurane by the rodent TRESKs but not by human TRESK. TRESK may be a target site for the mechanism of action of volatile anesthetics.
TRESK（TWIK相关脊髓钾通道）是串联孔结构域钾通道（K2P）家族中最新被鉴定的成员。人TRESK可被氟烷、异氟烷、七氟烷和地氟烷有效激活，使其成为目前已描述的对挥发性麻醉剂最敏感的K2P通道。在此，我们比较了啮齿动物版本的TRESK与其人类同源物的麻醉敏感性和药理调节作用。小鼠和大鼠TRESK所通过的电流在临床浓度下可被异氟烷增强，但效力明显低于人TRESK。与人类TRESK不同，啮齿动物的TRESK在生理范围内会受到酸性细胞外pH的强烈抑制。锌在低微摩尔浓度范围内可抑制两种啮齿动物TRESK所通过的电流，但对人TRESK无影响。在体内具有立体选择性麻醉效力的异氟烷对映体在体外可产生对啮齿动物TRESK的立体特异性增强作用。酰胺类局部麻醉剂抑制啮齿动物TRESK的浓度几乎比对人TRESK抑制浓度小10倍。这些结果确定了TRESK药理学中的种间差异和相似性。需要进一步表征TRESK的表达模式以了解它们在麻醉机制中的作用。
与人类TRESK相比，小鼠和大鼠的TRESK（TWIK相关脊髓钾通道）具有不同的药理反应。特别是，我们发现啮齿动物TRESK对异氟烷的反应存在立体特异性差异，但人类TRESK没有。TRESK可能是挥发性麻醉剂作用机制的靶点。
