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  • Review Article
  • Published:

The neuronal background K2P channels: focus on TREK1

Nature Reviews Neuroscience volume 8, pages 251–261 (2007)Cite this article

Key Points

  • Background K+ channels are dimers of K2P channel subunits, each of which is composed of four transmembrane segments and two P domains arranged in tandem.

  • The Aplysia serotonin-sensitive S-type K+ channel and the Lymnaea anaesthetic-sensitive K(An) channels are classical examples of background K+ channels.

  • Background K+ channels and their regulation by membrane-receptor-coupled second messengers, as well as pharmacological agents, influence neuronal resting membrane potential, action potential duration, membrane input resistance and, consequently, neurotransmitter release.

  • K2P channels diverge from the constant-field Goldman–Hodgkin–Katz (GHK) current formulation and are characterized by complex permeation and gating mechanisms.

  • TREK1 can be activated by mechanical stimulation, intracellular acidosis and warm temperature, thus qualifying as a polymodal sensory ion channel integrating multiple physical and chemical stimuli.

  • Besides its activation by physical stimuli, TREK1 is also upmodulated by various chemical stimuli including cellular lipids and volatile general anaesthetics.

  • Recent evidence suggests that both mechanical and lipid activations of TREK1 may be functionally linked. The proposed model states that a tight dynamic interaction of the cytosolic carboxy-terminal domain of TREK1 with the inner leaflet of the plasma membrane is central to the mechanism of channel gating and regulation by membrane receptors/second messenger pathways.

  • TREK1 is downmodulated by the stimulation of both Gs- and Gq-coupled membrane receptors. Recent studies have identified the second messenger pathways involved in this regulation, including phosphorylation pathways and PtdIns(4,5)P2 hydrolysis.

  • The Trek1−/− mutant mice are healthy, fertile and do not display any visible morphological difference. However, recent studies indicate a central role for TREK1 in anaesthesia, neuroprotection, pain perception and depression.

  • Both the Aplysia S-type K+ channel and mammalian TREK1 are involved in controlling the excitability of presynaptic neurons through the pathway mediated by serotonin, cyclic AMP and protein kinase A. However, in the dorsal raphé neurons, serotonin probably opens TREK1 though the Gi/o pathway, whereas serotonin closes the S-type K+ channel through the Gs pathway in molluscan sensory neurons.

Abstract

Two-pore-domain K+ (K2P) channel subunits are made up of four transmembrane segments and two pore-forming domains that are arranged in tandem and function as either homo- or heterodimeric channels. This structural motif is associated with unusual gating properties, including background channel activity and sensitivity to membrane stretch. Moreover, K2P channels are modulated by a variety of cellular lipids and pharmacological agents, including polyunsaturated fatty acids and volatile general anaesthetics. Recent in vivo studies have demonstrated that TREK1, the most thoroughly studied K2P channel, has a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain and depression.

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Figure 1: Diversity and structural properties of the human K2P channels.
Figure 2: Polymodal activation of TREK1 by physical and chemical stimuli.
Figure 3: Modulation of TREK1 by phosphatidylinositol-4,5-bisphosphate.
Figure 4: TREK1 is involved in polymodal pain perception.
Figure 5: Role of TREK1 in general anaesthesia and neuroprotection.
Figure 6: Role of TREK1 in feedback inhibition of serotonergic dorsal raphé neurons and the response to antidepressants.

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Acknowledgements

I am grateful to the ANR 2005 Cardiovasculaire-obésité-diabète, to the Association for Information and Research on Genetic Kidney Disease France, to the Fondation del Duca, to the Fondation de France, to the Fondation de la Recherche Médicale, to EEC Marie-Curie fellowships, to INSERM and to CNRS for support. I wish to thank A. Patel, S. Siegelbaum and E. Kandel for critical reading of this manuscript. I am grateful to M. Lazdunski and colleagues for helpful and stimulating discussions. Finally, I would like to thank the reviewers of this manuscript for their constructive input.

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Glossary

P domain

A short amino acid segment between two transmembrane helices that dips into the membrane without fully crossing it.

Selectivity filter

The sequence that determines K+ selectivity of K+ channels. The primary sequence of the P loop of most K+ channels has the signature sequence Thr–Val–Gly–Tyr–Gly.

Permeability ratio

The relative permeability of an ion channel for a particular monovalent cation. A given ion channel can allow the passage of related ionic species, although not all with the same ease.

Rectification

The property whereby current through a channel does not flow with the same ease from the inside as from the outside.

Inward rectifiers

Channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence upon hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.

Outward rectifiers

Channels that allow current to flow more easily out of the cell. Voltage-gated K+ channels are outward rectifiers that shape the action potential duration.

Intracellular acidosis

A decrease in intracellular pH that occurs, for example, during brain ischaemia.

Cell-attached patch configuration

Recording configuration in which the patch of membrane at the tip of the recording electrode is not excised but remains attached to the cell. This configuration allows the measurement of the current flowing through the ion channels embedded in the electrically isolated membrane patch.

Inside-out patch configuration

Recording configuration in which the patch of membrane at the tip of the patch-clamp electrode is excised from the cell. The intracellular side of the channel is exposed to the bathing solution.

Desensitization

Decrease in the activity of a protein during maintained stimulation.

Inner leaflet

The inner layer of phospholipids in the plasma membrane.

Polar head

Hydrophilic charged groups such as choline, ethanolamine, serine or inositol, bound to glycerol phosphate in membrane phospholipids.

Amphipaths

A molecule with both hydrophobic and hydrophilic surfaces.

Outside-out patch configuration

A variant of the patch-clamp technique, in which a patch of plasma membrane is excised from the cell. The outside of the membrane is exposed to the bathing solution.

Polymodal C-fibres

Non-myelinated axons characterized by a slow conduction. Polymodal nociceptors are activated by high intensity mechanical, chemical and thermal stimuli, involving non-myelinated C-fibres conducting delayed pain.

Allodynia

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

Porsolt forced swim test

A method to estimate behavioural despair in a stressful and inescapable situation. Mice rapidly adopt a characteristic immobile posture when they are forced to swim in a water tank. Immobility is considered to be a state of 'lowered mood' in which the animal has given up hope of finding an exit and is resigned to the stressful situation.

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Honoré, E. The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8, 251–261 (2007). https://doi.org/10.1038/nrn2117

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