Noninactivating tandem pore domain potassium channels as attractive targets for general anesthetics.

T he sites in the central nervous system where inhaled anesthetics exert their clinical effects remain to be defined. During the past two decades, most investigators in the field have shifted away from a nonspecific plasma membrane lipid site of action towards direct interactions with membrane proteins or even globular proteins. Currently, favored targets include ligand-gated ion channels, such as the -aminobutyric acid type A receptor, the glycine receptor, and the excitatory ionotropic glutamate receptor that is sensitive to N-methyl-d-aspartate (1). Enhancement of chloride ion conductance through the -aminobutyric acid type A or glycine receptor occurs in the presence of a number of inhaled anesthetics, and the resulting hyperpolarization of the plasma membrane is consistent with decreased neuronal activity. In addition, several inhaled anesthetics inhibit the excitatory N-methyl-d-aspartate receptor, which is also predicted to lead to decreased neuronal activity. Another plausible group of targets for general anesthetics are the background potassium channels examined in the paper by Shin and Winegar (2) in this issue of Anesthesia & Analgesia. The activity of these background potassium channels was enhanced by halothane, isoflurane, and sevoflurane in whole-cell patch-clamp experiments on cultured cerebellar granule neurons from 7-day-old Sprague-Dawley rats. Such increased conductivity through these background potassium channels in the presence of inhaled anesthetics will hyperpolarize the plasma membrane and result in decreased neuronal activity. Nicoll and Madison (3) initially noted the ability of general anesthetics to hyperpolarize frog motoneurons and rat hippocampal CA1 pyramidal cells by increasing potassium conductance. These background or tandem pore (P) domain potassium channels are a recently described family of membrane proteins that mediate baseline or leak currents, set the resting membrane potential, and thereby influence the likelihood of neuronal action potential generation. Potassium channels are the most diversified of the various ion channels, with more than 70 different types present in the human genome. Potassium channels have a characteristic conserved P domain in their primary sequences (4) that forms part of the ion channel itself and determines potassium selectivity over other ions and either two, four, or six transmembrane domains. Patel et al. (5) identified a family of mammalian potassium channels with a basic architecture consisting of two P domains in tandem and four transmembrane segments. The native functional form of these channels is thought to be a dimeric structure containing a total of four P domains. Voltage independence coupled with absent activation and inactivation kinetics are characteristics of conductances referred to as leak or background conductances. The five representatives of this family are designated TWIK-1, TASK, TREK-1, TRAAK, and TALK-1, where the first letter indicates tandem P domain. TWIK-1 is a weakly inward-rectifying K channel, and TASK (acid sensitive) is a background outward-rectifier (outward channel conductance increases with depolarization more than inward currents with hyperpolarization) potassium channel whose activity is inhibited by low pH. This potassium channel is very sensitive to changes in extracellular pH within the physiological range, exhibiting 10% of the maximal current at a pH value of 6.7 compared with 90% at a pH value of 7.7 (6). TREK-1 (TWIK-1 related K channel) and TRAAK (TWIK-1 related arachidonic acid-stimulated K channel) are both background outward-rectifier potassium channels that are activated by polyunsaturated fatty acids, including arachidonic acid. The current model explaining how polyunsaturated fatty acids alter channel activity involves changes in the curvature of the lipid bilayer rather than direct interactions with the channel protein (5). The alkaline-activated tandem P domain potassium channel TALK-1 is primarily expressed in the pancreas (7). This family of potassium Supported, in part, by NIH grants GM55876 and GM65218. Accepted for publication January 14, 2003. Address correspondence and reprint requests to Jonas S. Johansson, MD, PhD, 319C John Morgan Building, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104. Address e-mail to [email protected].