The TREK K2P channels and their role in general anaesthesia and neuroprotection

doi:10.1016/j.tips.2004.09.003

Trends in Pharmacological Sciences

Volume 25, Issue 11, November 2004, Pages 601-608

https://doi.org/10.1016/j.tips.2004.09.003 Get rights and content

Two-pore-domain K⁺ (K_2P) channels are a diverse and highly regulated superfamily of channels that are thought to provide baseline regulation of membrane excitability. Of these, the TREK channels are expressed highly in the human CNS, and can be activated by temperature, membrane stretch and internal acidosis. In addition, TREK channels are sensitively activated by certain polyunsaturated fatty acids that have been shown to have neuroprotective activity and by volatile and gaseous general anaesthetics. New data derived from studies of knockout animals suggest that TREK-1 might have an important role in the general anaesthetic properties of volatile agents, such as halothane, and provide an explanation for the neuroprotective properties of polyunsaturated fatty acids.

Section snippets

Molecular and functional properties of TREK-1

The class of mammalian K_2P channel subunits, comprising four transmembrane segments and two pore (P) domains in tandem, includes 15 members 4, 15 (Figure 1 and Figure 2a). The P domains are part of the K⁺ conduction pathway [16]. Functional K_2P channels are dimers of subunits and heteromultimerization occurs 17, 18. Although the 2P-domain K⁺ channel subunits display the same structural motif, they share only moderate sequence homology outside their P regions [4] (Figure 1).

Human TREK-1 mRNA is

Opening of TREK-1 by volatile general anaesthetics

TREK-1 and its functional homologue TREK-2 are opened by the volatile anaesthetics chloroform, diethyl ether, halothane and isoflurane in transfected mammalian cells 3, 10, 22 (Figure 2b). Opening of these channels by these anaesthetics induces cell hyperpolarization (Figure 2c). Interestingly, the other structurally and functionally related 2P-domain K⁺ channel TRAAK (Figure 1) is insensitive to volatile anaesthetics [3]. In excised outside-out patches, mouse TREK-1 channel is reversibly

Opening of TREK-1 by gaseous anaesthetics

Nitrous oxide and xenon are known for their potent analgesic action, in addition to their euphoric and neuroprotective effects, and have been shown to inhibit the NMDA receptor 41, 42. Recently, it was demonstrated that clinical concentrations of nitrous oxide and xenon also open TREK-1, further suggesting that this K⁺ channel might have a role in the general anaesthesia and neuroprotection [11] caused by these agents. In the presence of anaesthetic concentrations that are similar to MAC

Opening of TREK-1 by non-volatile anaesthetics

Chloral hydrate (CH) is used clinically as a sedative in pediatric patients and as an anaesthetic in laboratory animals. It is rapidly metabolised to trichloroethanol (TCE) within minutes of administration and the pharmacological effect of CH is attributed to TCE [12]. Recently, both CH and TCE, at pharmacologically relevant concentrations, were shown to open TREK-1 and TRAAK [12]. CH produced a transient activation of TREK-1, whereas TRAAK exhibited no desensitization. The C-terminal domain of

In vivo evidence for a key role for TREK-1 in general anaesthesia

Riluzole has been shown to enhance the anaesthetic potencies of both isoflurane [43] and halothane [44], which suggest that TREK channels might be involved in anaesthesia. However, these data are difficult to interpret in molecular terms because the enhancement of anaesthetic potency by specific activators or inhibitors (which are often not as selective as supposed) might be due to effects on parallel pathways that are not involved in the actions of the anaesthetic in question.

Very recently,

Lipids, TREK-1 and neuroprotection

PUFAs, including linolenate (LIN) (C18:3), which is found in high quantities in vegetable oils, protect the rat brain against global ischaemia [52] (Figure 3a,b). By contrast, the saturated fatty acid palmitate (PAL) is not neuroprotective (Figure 3b). LIN is protective when administered either intracerebroventricularly or intravenously [52]. LIN also prevents neuronal cell death and paraplegia after transient spinal cord ischaemia in rats [53]. Neuroprotection by LIN, unlike PAL, has also been

Concluding remarks

There is mounting evidence that TREK-1 has an important role in the induction of general anaesthesia for several simple anaesthetics, with the recent data on TREK-1 knockout mice proving to be the most definitive, at least for the volatile agents. Moreover, opening of TREK-1 is clearly important to protect neurons against both ischaemic and epileptic insults. As new K_2P channel transgenic animals become available, the roles that other members of this intriguing family of ion channels have in

Acknowledgements

We would like to apologize to all colleagues whose work and reviews could not be acknowledged owing to text and citation limitations. E.H. thanks M. Lazdunski and A.J. Patel for stimulating discussion and continual support. E.H. is funded by the CNRS and the Foundation Paul Hamel and N.P.F. thanks the Medical Research Council (UK) and Carburos Metálicos for support. We also thank Alistair Mathie and Stephen Brickley for helpful comments on the manuscript.

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Trends in Pharmacological Sciences

The TREK K2P channels and their role in general anaesthesia and neuroprotection

Section snippets

Molecular and functional properties of TREK-1

Opening of TREK-1 by volatile general anaesthetics

Opening of TREK-1 by gaseous anaesthetics

Opening of TREK-1 by non-volatile anaesthetics

In vivo evidence for a key role for TREK-1 in general anaesthesia

Lipids, TREK-1 and neuroprotection

Concluding remarks

Acknowledgements

Trends Neurosci.

Trends Pharmacol. Sci.

J. Biol. Chem.

Neuropharmacology

J. Biol. Chem.

J. Biol. Chem.

Brain Res. Mol. Brain Res.

Neuroscience

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuropharmacology

J. Vasc. Surg.

Neuroscience

Trends Pharmacol. Sci.

Br. J. Anaesth.

General anaesthetics hyperpolarize neurons in the vertebrate central nervous system

Science

Volatile general anaesthetics activate a novel neuronal K+ current

Nature

Inhalational anaesthetics activate two-pore-domain background K+ channels

Nat. Neurosci.

Molecular and functional properties of two-pore-domain potassium channels

Am. J. Physiol. Renal Physiol.

Potassium leak channels and the KCNK family of two-P-domain subunits

Nat. Rev. Neurosci.

Two-pore-Domain (KCNK) potassium channels: dynamic roles in neuronal function

Neuroscientist

Update on tandem pore 2P domain K+ channels

Curr. Drug Targets

Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane

Mol. Pharmacol.

Anesthetic-sensitive 2P domain K+ channels

Anesthesiology

TREK-1, a K+ channel involved in neuroprotection and general anesthesia

EMBO J.

The TREK K_2P channels and their role in general anaesthesia and neuroprotection

Volatile general anaesthetics activate a novel neuronal K⁺ current

Inhalational anaesthetics activate two-pore-domain background K⁺ channels

Update on tandem pore 2P domain K⁺ channels

Two-pore-domain K⁺ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane

Anesthetic-sensitive 2P domain K⁺ channels

TREK-1, a K⁺ channel involved in neuroprotection and general anesthesia