ReviewPharmacology of neuronal background potassium channels
Introduction
The existence of background conductances in neurones was originally postulated by Hodgkin and Huxley (1952). In addition to the voltage-sensitive Na+ and K+ currents involved in action potential generation, these authors proposed a voltage-insensitive leak current as the basis of the resting membrane potential. Subsequently, it was shown that the resting potential in different types of neurones depended primarily on K+-selective currents showing a relative insensitivity to classical K+ channel blockers (Baker et al., 1987, Jones, 1989, Premkumar et al., 1990, Shen et al., 1992, Koh et al., 1992, Koyano et al., 1992, Theander et al., 1996). For example, in myelinated nerve, different K+ conductances can be successively removed by sequential applications of TEA, 4-AP and Cs+; but treated axons still exhibit strong outward rectification suggesting that residual K+ conductance is present. The conductance, which is believed to set the resting potential, is voltage-independent but outwardly rectifying, as expected from constant field theory (Baker et al., 1987). This type of current is easily distinguishable from the voltage-sensitive inwardly rectifying K+ currents that play a similar role in cardiac and skeletal muscle cells (Hille, 1992). Until recently, neuronal background currents received only a fraction of the attention that was devoted to the voltage-gated and Ca2+- sensitive K+ currents, but the recent cloning of a new family of K+ channels has permitted a detailed characterisation of the electrophysiological and pharmacological properties, and regulation of these currents (for reviews see Lesage and Lazdunski, 2000, Patel and Honoré, 2001). Electrophysiology of the corresponding conductances in vivo, in association with in situ hybridization and immunohistochemistry, has revealed a broad distribution of these channels in the nervous system. Another major result is the tight and specific regulation of these channels by a variety of physical and chemical stimuli, suggesting that precise tuning of their activity is associated with cell-specific regulation of neuronal activity.
Section snippets
The two-pore- domain K+ channels
K+ channels form the largest family of ion channels. More than 70 genes encoding pore-forming subunits have been identified in the human genome. These subunits are organised into three main families according to their predicted membrane topology. The two largest families comprise subunits with six or two membrane-spanning segments and one pore (P) domain (Jan and Jan, 1997). These subunits assemble as homo- or heterotetramers to form active channels belonging to different functional groups
TASK channels in the nervous system
TASK1 (KCNK3) and TASK3 (KCNK9), together with the non-functional TASK5 (KCNK15) subunits, form a subfamily of structurally related channels (Fig. 1). They produce strong basal currents with all the characteristics of leak conductances. TASK currents display only little time- or voltage-dependence. Their activation and inactivation kinetics are very fast. These currents display an outward rectification that can be approximated by the Goldman–Hodgkin–Katz (GHK) current equation that predicts a
TREK channels in the nervous system
The TREK (TWIK-related K+ channels) subfamily comprises three subunits with related structural and electrophysiological properties (TREK1/KCNK2, TREK2/KCNK10, and TRAAK/KCNK4) (Fig. 1). TREK channels produce baseline currents similar to TASK currents with a GHK outward rectification in physiological K+ conditions, and very fast activation and deactivation kinetics, as well as a relative insensitivity to the classical K+ channel blockers. However, whereas the basal activity of TASK channels is
Modulation of neuronal background K+ channels by clinically relevant compounds
Background K+ channels in Aplysia sensory neurones and in Lymnea pacemaker neurones are activated by volatile anaesthetics (Franks and Lieb, 1988, Winegar and Yost, 1998). This activation leads to membrane potential hyperpolarisation, suppressing action potential firing activity and neuronal transmission. Accordingly, the cloned TREK1 and TREK2, but not TRAAK, channels, are opened by low concentrations of diethylether, chloroform, halothane, and isofluorane, whereas TASK1 and TASK3 channels are
Conclusion
Our knowledge of physiological and pathophysiological roles of neuronal background K+ channels has greatly benefited from the cloning and functional characterization of two-P-domain K+ channels, but it still remains very limited. Mutations in one-P-domain K+ channel genes have been associated with hereditary diseases (potassium channelopathies) of the nervous system. The first attempts to associate such diseases with mutations in background two-P-domain K+ channels have not yet been successful (
Acknowledgements
Thanks are due to Professor Michel Lazdunski for his continuous support, to Steve Balt for careful reading of the manuscript and Franck Aguila for the illustrations.
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