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

被引：413

作者：

Heurteaux, C ^{[1
]}

Guy, N ^{[1
]}

Laigle, C ^{[1
]}

Blondeau, N ^{[1
]}

Duprat, F ^{[1
]}

Mazzuca, M ^{[1
]}

Lang-Lazdunski, L ^{[1
]}

Widmann, C ^{[1
]}

Zanzouri, M ^{[1
]}

Romey, G ^{[1
]}

Lazdunski, M ^{[1
]}

机构：

[1] Inst Paul Hamel, CNRS, UMR 6097, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France

来源：

EMBO JOURNAL | 2004年 / 23卷 / 13期

关键词：

epilepsy; ischemia; neuroprotection; 2P domain K+ channel; volatile anesthetics;

D O I：

10.1038/sj.emboj.7600234

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2684 / 2695

页数：12

共 54 条

[1] Polyunsaturated fatty acids induce ischemic and epileptic tolerance [J].

Blondeau, N ;

Widmann, C ;

Lazdunski, M ;

Heurteaux, C .

NEUROSCIENCE, 2002, 109 (02) :231-241

[2] A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures [J].

Blondeau, N ;

Lauritzen, I ;

Widmann, C ;

Lazdunski, M ;

Heurteaux, C .

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2002, 22 (07) :821-834

[3] METABOTROPIC GLUTAMATE RECEPTORS - AN ORIGINAL FAMILY OF G-PROTEIN-COUPLED RECEPTORS [J].

BOCKAERT, J ;

PIN, J ;

FAGNI, L .

FUNDAMENTAL & CLINICAL PHARMACOLOGY, 1993, 7 (09) :473-485

[4] Group I metabotropic glutamate receptors: Implications for brain diseases [J].

Bordi, F ;

Ugolini, A .

PROGRESS IN NEUROBIOLOGY, 1999, 59 (01) :55-79

[5] Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance [J].

Brickley, SG ;

Revilla, V ;

Cull-Candy, SG ;

Wisden, W ;

Farrant, M .

NATURE, 2001, 409 (6816) :88-92

[6] Drug therapy: Mechanisms of actions of inhaled anesthetics [J].

Campagna, JA ;

Miller, KW ;

Forman, SA .

NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (21) :2110-2124

[7] Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels [J].

Chemin, J ;

Girard, C ;

Duprat, F ;

Lesage, F ;

Romey, G ;

Lazdunski, M .

EMBO JOURNAL, 2003, 22 (20) :5403-5411

[8]

Duprat F, 2000, MOL PHARMACOL, V57, P906

[9]

Ettaiche M, 1999, INVEST OPHTH VIS SCI, V40, P729

[10] Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons [J].

Fagni, L ;

Chavis, P ;

Ango, F ;

Bockaert, J .

TRENDS IN NEUROSCIENCES, 2000, 23 (02) :80-88

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