TREK-1, a K+ channel involved in neuroprotection and general anesthesia.
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.
Heurteaux
C
C
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Institut Paul Hamel, Sophia-Antipolis, Valbonne, France.
Guy
N
N
Laigle
C
C
Blondeau
N
N
Duprat
F
F
Mazzuca
M
M
Lang-Lazdunski
L
L
Widmann
C
C
Zanzouri
M
M
Romey
G
G
Lazdunski
M
M
D000768:Anesthesia, General; D018681:Anesthetics, General / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000517:prevention & control; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004827:Epilepsy / Q000517:prevention & control; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006579:Heterozygote; D006720:Homozygote; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020760:Spinal Cord Ischemia / Q000517:prevention & control
D018681:Anesthetics, General; D005231:Fatty Acids, Unsaturated; D008246:Lysophospholipids; D018696:Neuroprotective Agents; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D000242:Cyclic AMP; D043802:GTP-Binding Protein alpha Subunits, Gq-G11