Motoneuronal TASK Channels Contribute to Immobilizing Effects of Inhalational General Anesthetics

Abstract

General anesthetics cause sedation, hypnosis, and immobilization via CNS mechanisms that remain incompletely understood; contributions of particular anesthetic targets in specific neural pathways remain largely unexplored. Among potential molecular targets for mediating anesthetic actions, members of the TASK subgroup [TASK-1 (K2P3.1) and TASK-3 (K2P9.1)] of background K ϩ channels are appealing candidates since they are expressed in CNS sites relevant to anesthetic actions and activated by clinically relevant concentrations of inhaled anesthetics. Here, we used global and conditional TASK channel single and double subunit knock-out mice to demonstrate definitively that TASK channels account for motoneuronal, anesthetic-activated K ϩ currents and to test their contributions to sedative, hypnotic, and immobilizing anesthetic actions. In motoneurons from all knock-out mice lines, TASK-like currents were reduced and cells were less sensitive to hyperpolarizing effects of halothane and isoflurane. In an immobilization assay, higher concentrations of both halothane and isoflurane were required to render TASK knock-out animals unresponsive to a tail pinch; in assays of sedation (loss of movement) and hypnosis (loss-of-righting reflex), TASK knock-out mice showed a modest decrease in sensitivity, and only for halothane. In conditional knock-out mice, with TASK channel deletion restricted to cholinergic neurons, immobilizing actions of the inhaled anesthetics and sedative effects of halothane were reduced to the same extent as in global knock-out lines. These data indicate that TASK channels in cholinergic neurons are molecular substrates for select actions of inhaled anesthetics; for immobilization, which is spinally mediated, these data implicate motoneurons as the likely neuronal substrates.

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

“…TASK-1 and TASK-3 channels are widely expressed in various tissues, including the cerebral cortex (Callahan et al, 2004), the brainstem pre-Botzinger and retrotrapezoid regions (Mulkey et al, 2007;Koizumi et al, 2010), the carotid bodies (Buckler et al, 2000), hypoglossal and spinal cord motor neurons (Lazarenko et al, 2010), pulmonary artery smooth muscle (Olschewski et al, 2006), the adrenal cortex (Czirjak and Enyedi, 2002), and the atrium of the heart (Limberg et al, 2011). The TASK-3 channel is also overexpressed in a variety of cancers and confers hypoxia resistance on tumors (Mu et al, 2003).…”

Immunocytochemical Localization of TASK-3 Channels in Rat Motor Neurons

“…Conditional knockout mice that lack TASK-1 and TASK-3 channels in cholinergic neurons required higher concentrations of halothane and isoflurane to immobilize the animals (Lazarenko et al 2010). It is tempting to speculate that this spinal-mediated paralysis might be a mechanism that could also relate TASK channel dysfunction to motor neuron diseases.…”

“…current in motor neurons cannot be explained by the known presence of the inwardly rectifying Kir2.2 and Kir2.4 channels (Karschin et al 1996;Töpert et al 1998;Prüss et al 2005). This current is strongly pH-sensitive, activated by inhalational anesthetics, and inhibited by Gq-coupled receptors, which is indicative of TASK currents Talley et al 2000); (4) TASK-like currents in motor neurons based on homodimeric or heterodimeric TASK-1 and TASK-3 complexes, regulate cellular excitability (Larkman and Perkins 2005) and contribute to immobilizing effects of anesthetics (Patel et al 1999;Sirois et al 2000;Lazarenko et al 2010); (5) TASK currents are strongly regulated by signals which are well known to participate in motor neuron excitability, such as Gq-alpha-protein coupled receptors for monoamines and other neurotransmitters Berg et al 2004;Perrier et al 2003); (6) TASK-3 channels were implicated in mitochondrial dysfunction, an important mechanism in ALS pathophysiology (Bittner et al 2010).…”

Covalent Modification of a Volatile Anesthetic Regulatory Site Activates TASK-3 (KCNK9) Tandem-Pore Potassium Channels

“…Studies with TASK-3-knockout mice confirmed the relevance of this channel. Compared with wildtype control mice, TASK-3-knockout mice require increased amounts of volatile anesthesia for loss of consciousness and immobility, are slower to lose consciousness, and, in the absence of anesthesia, display fragmented sleep (Pang et al, 2009;Lazarenko et al, 2010).…”