TREK‐1 is a two‐pore‐domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids and lysophospholipids. It is inhibited by neurotransmitters that produce an increase in intracellular cAMP and by those that activate the Gq protein pathway. TREK‐1 is also activated by volatile anesthetics and has been suggested to be an important target in the action of these drugs. Using mice with a disrupted TREK‐1 gene, we now show that TREK‐1 has an important role in neuroprotection against epilepsy and brain and spinal chord ischemia. Trek1−/− mice display an increased sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty acids, which is impressive in Trek1+/+ mice, disappears in Trek1−/− mice indicating a central role of TREK‐1 in this process. Trek1−/− mice are also resistant to anesthesia by volatile anesthetics. TREK‐1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology.

The TREK‐1 channel is a temperature‐sensitive, osmosensitive and mechano‐gated K+ channel with a regulation by Gs and Gq coupled receptors. This paper demonstrates that TREK‐1 qualifies as one of the molecular sensors involved in pain perception. TREK‐1 is highly expressed in small sensory neurons, is present in both peptidergic and nonpeptidergic neurons and is extensively colocalized with TRPV1, the capsaicin‐activated nonselective ion channel. Mice with a disrupted TREK‐1 gene are more sensitive to painful heat sensations near the threshold between anoxious warmth and painful heat. This phenotype is associated with the primary sensory neuron, as polymodal C‐fibers were found to be more sensitive to heat in single fiber experiments. Knockout animals are more sensitive to low threshold mechanical stimuli and display an increased thermal and mechanical hyperalgesia in conditions of inflammation. They display a largely decreased pain response induced by osmotic changes particularly in prostaglandin E2‐sensitized animals. TREK‐1 appears as an important ion channel for polymodal pain perception and as an attractive target for the development of new analgesics.

Results reported in this work suggest a potential therapeutic value of polyunsaturated fatty acids for cerebral pathologies as previously proposed by others for cardiac diseases. We show that the polyunsaturated fatty acid linolenic acid prevents neuronal death in an animal model of transient global ischemia even when administered after the insult. Linolenic acid also protects animals treated with kainate against seizures and hippocampal lesions. The same effects have been observed in an in vitro model of seizure‐like activity using glutamatergic neurons and they have been shown to be associated with blockade of glutamatergic transmission by low concentrations of distinct polyunsaturated fatty acids. Our data suggest that the opening of background K+ channels, like TREK‐1 and TRAAK, which are activated by arachidonic acid and other polyunsaturated fatty acids such as docosahexaenoic acid and linolenic acid, is a significant factor in this neuroprotective effect. These channels are abundant in the brain where they are located both pre‐ and post‐synaptically, and are insensitive to saturated fatty acids, which offer no neuroprotection.