Discrete Change in Volatile Anesthetic Sensitivity in Mice with Inactivated Tandem Pore Potassium Ion Channel TRESK

Abstract

Backgrcound-We investigated the role of tandem pore domain potassium channel (K 2P ) TRESK in neurobehavioral function and volatile anesthetic sensitivity in genetically modified mice.Methods-Exon III of the mouse TRESK gene locus was deleted by homologous recombination using a targeting vector. The genotype of bred mice (wildtype, knockout or heterozygote) was determined using the polymerase chain reaction. Morphologic and behavioral evaluations of TRESK knockout mice were compared to wildtype littermates. Sensitivity of bred mice to isoflurane, halothane, sevoflurane and desflurane were studied by determining the minimum alveolar concentration preventing movement to tail clamping in 50% of each genotype.Results-TRESK knockout mice had normal development and behavior except for decreased number of inactive periods and increased thermal pain sensitivity (20% decrease in latency with hot plate test). TRESK knockout mice showed a statistically significant 8% increase in isoflurane minimum alveolar concentration compared to wildtype littermates; sensitivity to other volatile anesthetics was not significantly different. Spontaneous mortality of TRESK knockout mice following initial anesthesia testing was nearly threefold higher than that of wildtype littermates.Conclusions-TRESK alone is not critical for baseline central nervous system function but may contribute to the action of volatile anesthetics. The inhomogenous change in anesthetic sensitivity corroborates findings in other K 2P knockout mice and supports the idea that the mechanism of volatile anesthetic action involves multiple targets. Although it was not shown in this study, a compensatory effect by other K 2P channels may also contribute to these observations.

Determination of Minimum Alveolar Concentration for Isoflurane and Sevoflurane in a Rodent Model of Human Metabolic Syndrome

“…The knockout mice lacking TRESK showed decreased sensitivity and hence increased MAC for isoflurane. 26 However, TRESK inactivation did not affect the sensitivity to sevoflurane, halothane and desflurane. 26 Collectively, the present results along with the published literature support a genetic basis for differences in anesthetic sensitivity that is agent-specific.…”

“…26 However, TRESK inactivation did not affect the sensitivity to sevoflurane, halothane and desflurane. 26 Collectively, the present results along with the published literature support a genetic basis for differences in anesthetic sensitivity that is agent-specific. Future studies involving genetic manipulations of ion channels in LCR and HCR rats may provide further support to an underlying genetic basis for the differential anesthetic sensitivity between LCR and HCR rats.…”

“…23 Furthermore, genetic manipulations affecting ion channels have been shown to alter anesthetic sensitivity. 24,25 Recently, Chae et al 26 reported a differential effect of inactivation of TRESK (two pore potassium channel) gene on anesthetic sensitivity. The knockout mice lacking TRESK showed decreased sensitivity and hence increased MAC for isoflurane.…”

The LQLP Calcineurin Docking Site Is a Major Determinant of the Calcium-dependent Activation of Human TRESK Background K+ Channel

“…TRESK is present in the plasma membrane of the cell body, as its single channel openings were detected in excised membrane patches of dorsal root ganglion (DRG) neurons (27), and perikaryons isolated form TRESK knock-out mice showed altered electrophysiological properties (28). TRESK function appeared to be partially compensated by other K ϩ channels in these cells (28), and a TRESK-related phenotype has not yet been described in the knock-out animals apart from a slightly increased mortality rate following anesthesia (33). Rat sciatic nerve axotomy induced hyperexcitability of nociceptive DRG neurons by decreasing TRESK mRNA expression (30), and the mutation of human TRESK was reported to be linked to a rare form of familial migraine (7), suggesting a role for the channel in pain disorders (31, 34 -36).…”

Protein Kinase A and C Regulate Leak Potassium Currents in Freshly Isolated Vascular Myocytes from the Aorta

“…Known K + channel blockers do not inhibit K2P channels [8], [9], [10], [11], [12], [13]. K2P channels are regulated by a number of different G protein-coupled receptor (GPCR) pathways [14], [15].…”