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

Abstract

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.

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

“…Originally, human TRESK was found exclusively in the spinal cord (299). Later TRESK mRNA was suggested to be more abundant in the human brain (205). Mouse TRESK was shown to be expressed in the cerebrum, cerebellum, brain stem, spinal cord, and testis (70).…”

Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels

“…Only three subtypes showed significant inhibition, including KCNK3, KCNK9 and KCNK18 (also known as TASK-1, TASK-3 and TRESK, respectively; Fig. 3a,b), all of which are targeted by volatile and local anesthetics 17,18,[22][23][24][25][26][27] . The greatest potency was observed with KCNK3 and KCNK18 (IC 50 = 30.3 ± 4.9 and 50.2 ± 1.9 μM, respectively), whereas KCNK9 was much less sensitive (IC 50 = 450 ± 30.1 μM) (Fig.…”

Effects of Different Types of Anesthetic Agents on Cellular Protein Kinase C-γ Dynamics in Mouse Brain

“…In the present study, we evaluated the effects of anesthetics on the distribution of PKC-␥ and p-PKC-␥ in the membrane and synaptosome fraction obtained from brain just after the mice had succumbed to anesthesia. Because PKC has been shown to be degraded after being transferred to the plasma membrane [10] , we paid particular attention to the temperature during the preparation of brain cell fractions as described in Material and Methods to avoid the effects of degradation. We found a statistically significant difference only in the 2 MAC sevoflurane-treated group, but both volatile anesthetics tended to show reduced immunoreactivity for PKC-␥ in the P2 fraction.…”