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ANESTHETIC PHARMACOLOGY

Potent Activation of the Human Tandem Pore Domain K Channel TRESK with Clinical Concentrations of Volatile Anesthetics

Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California

Address correspondence and reprint requests to C. Spencer Yost, MD, Department of Anesthesia and Perioperative Care, 513 Parnassus Ave., Room S-261, Box 0542, San Francisco, CA 94143. Address e-mail to spyost{at}itsa.ucsf.edu

The tandem pore domain K channel family mediates background K currents present in excitable cells. Currents passed by certain members of the family are enhanced by volatile anesthetics, thus suggesting a novel mechanism of anesthesia. The newest member of the family, termed TRESK (TWIK [tandem pore domain weak inward rectifying channel]-related spinal cord K channel), has not been studied for anesthetic sensitivity. We isolated the coding sequence for TRESK from human spinal cord RNA and functionally expressed it in Xenopus oocytes and transfected COS-7 cells. With both whole-cell voltage-clamp and patch-clamp recording, TRESK currents increased up to three-fold by clinical concentrations of isoflurane, halothane, sevoflurane, and desflurane. Nonanesthetics (nonimmobilizers) had no effect on TRESK. Various IV anesthetics, including etomidate, thiopental, and propofol, have a minimal effect on TRESK currents. Amide and ester local anesthetics inhibit TRESK in a concentration-dependent manner but at concentrations generally larger than those that inhibit other tandem pore domain K channels. We also determined that TRESK is found not only in spinal cord, but also in human brain RNA. These results identify TRESK as a target of volatile anesthetics and suggest a role for this background K channel in mediating the effects of inhaled anesthetics in the central nervous system.

IMPLICATIONS: Enhancement of background K channel currents by volatile anesthetics may contribute to neuronal depression during anesthesia. Currents passed by a newly discovered human background K channel, TWIK-related spinal cord K channel, are strongly enhanced by volatile anesthetics in the clinical range, suggesting a role for it in volatile anesthetic mechanisms.

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