Review
Lipid and mechano-gated 2P domain K+ channels

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Abstract

The two pore domain K+ channels TREK and TRAAK are opened by membrane stretch. The activating mechanical force comes from the bilayer membrane and is independent of the cytoskeleton. Emerging work shows that mechano-gated TREK and TRAAK are opened by various lipids, including long chain polyunsaturated anionic fatty acids and neutral cone-shaped lysophospholipids. TREK-1 shares the properties of the Aplysia neuronal S channel, a presynaptic background K+ channel involved in behavioral sensitization, a simple form of learning.

Introduction

K+ channels form the largest family of ion channels with more than 70 genes identified in the human genome. Background K+ selective channels, whose actions are not voltage- or time-dependent, play an essential role in setting the neuronal membrane potential, in tuning the action potential duration and in modulating the membrane input resistance. In the marine snail Aplysia, the serotonin-sensitive S-type background K+ channel is responsible for the control of presynaptic facilitation of transmitter release that underlies behavioral sensitization, a simple form of learning 1., 2.. Modulation of background K+ channels by neurotransmitters and second messengers is thus central to the regulation of synaptic function [3].

Mammalian K+ channel subunits can be divided into three main structural classes, comprising two, four or six transmembrane segments (TMS). The common feature of all K+ channels is the presence of a conserved motif called the P domain (pore domain or K+ channel signature), which is part of the K+ conduction pathway [4••]. The two TMS (which include the inward rectifiers) and six TMS (which include the voltage-gated outward-rectifiers) classes comprise a single P domain, whereas the most recently discovered class, the four TMS, is characterized by the presence of tandem P domains (Fig. 1a; [5]). Functional two and six TMS K+ channels are tetramers of pore-forming subunits, whereas the four TMS class probably forms dimers [6].

The novel class of mammalian four TMS K+ channel subunits consists so far of 14 members. Although these subunits display the same structural motif, with four TMS and two P domains (4 TMS/2P), an extended extracellular loop between the first TMS and the first P domain and both their amino- and carboxy-termini inside the cell, they only share low sequence identity (Fig. 1). This novel structural motif is associated with unusual functional properties. The 2P domain K+ channels can be divided into five main functional classes: one, the weak inward rectifiers, TWIK-1 and TWIK-2 (KCNK7 does not express) 5., 7., 8., 9., 10.; two, the acid-sensitive outward rectifiers, TASK-1, TASK-2 and TASK-3 11., 12., 13., 14., 15., 16. (KT3.3 remains to be expressed); three, the lipid-sensitive mechano-gated K+ channels, TREK-1, TREK-2 and TRAAK 17., 18., 19••., 20.; four, the halothane-inhibited 2 P domain K+ channel THIK-1 (THIK-2 does not express); [21] and five, the alkaline-activated background K+ channels TALK-1 and TALK-2 (see Update). No evidence for heteromultimerization has been reported. In this review we will concentrate on the functional and physiological properties of the 4 TMS/2 P domain mechano-gated K+ channels.

Section snippets

Mechano-gated 2P domain K+ channels

TREK and TRAAK subunits share the closest sequence identity, ranging from 63% to 78% 17., 18., 19••., 20.. The genomic organization of TREK-1 (1q41), TREK-2 (14q31) and TRAAK (11q13) is very similar, suggesting that they may have arisen by gene duplication from a common ancestor [20]. Human TREK-1, TREK-2 and TRAAK are consistently found in the brain, but are absent from the heart ([20]; Fig. 1c). These channels have a particularly abundant and overlapping expression in certain regions of the

Polyunsaturated fatty acids and anionic amphipaths open the mechano-gated 2P domain K+ channels

TREK-1, TREK-2 and TRAAK are reversibly opened by polyunsaturated fatty acids (PUFA) including arachidonic acid (17., 19••., 20., 27.; Fig. 2a and b). Activation of these channels is observed in excised patch configurations and in the presence of cyclo-oxygenase and lipoxygenase inhibitors, indicating that the effect is independent of AA metabolism 19••., 27.. The threshold concentration of PUFA is 100 nM, and the effect does not saturate, even at concentrations as high as 100 μM 17., 19••..

Conic neutral lysophospholipids are openers of TREK and TRAAK channels

Lysophospholipids (LP), including lysophosphatidylcholine (LPC), unlike phospholipids (PC), open TREK and TRAAK channels (20., 30••.; Fig. 3a–c). The threshold concentration for opening is 100 nM and no saturation is obtained at high concentration [30••]. At low doses, AA and LPC produce additive activation. The effect of LP is critically dependent on the length of the carbonyl chain (longer than 10 carbons) and the presence of a large polar head (choline or inositol) ([30••]; Fig. 3c).

Conclusions

Emerging work shows that the mechano-gated 2P domain K+ channels TREK and TRAAK are opened by various lipids, including PUFA and LP 17., 19••., 20., 26., 27., 30••.. TREK channels share all the biophysical, pharmacological and regulation properties of the Aplysia S-type K+ channel involved in presynaptic facilitation 1., 2., 39.. Interestingly, both the S channel and TREK-1, unlike TRAAK, are opened by inhalational anesthetics, suggesting that they are involved in general anesthesia 25••., 40.,

Update

A recent study details the pattern of mRNA expression of 2P domain K+ channels in human central and peripheral nervous systems [42]. The distribution of TREK-1 at the protein level has recently been studied by immunocytochemistry [43]. TREK-1 is predominantly expressed in GABAergic interneurons of the hippocampus, isocortex, thalamus and cerebellum. GABAergic interneurons of the cortex and the hippocampus have, similarly to the Aplysia S channel, a prominent role in cognition, learning and

Acknowledgements

This work was supported by the Centre National de la Recherche Scientifique (CNRS). We wish to thank V Lopez for excellent technical assistance.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • •of special interest

  • ••of outstanding interest

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