Alloui Abdelkrim, Zimmermann Katharina, Mamet Julien, Duprat Fabrice, Noël Jacques, Chemin Jean, Guy Nicolas, Blondeau Nicolas, Voilley Nicolas, Rubat-Coudert Catherine, Borsotto Marc, Romey Georges, Heurteaux Catherine, Reeh Peter, Eschalier Alain, Lazdunski Michel
Laboratoire de Pharmacologie Médicale EA 3848 INSERM/Faculté de Médecine/CHU, Clermont-Ferrand, France.
EMBO J. 2006 Jun 7;25(11):2368-76. doi: 10.1038/sj.emboj.7601116. Epub 2006 May 4.
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.
TREK-1通道是一种对温度、渗透压敏感且受机械门控的钾离子通道,受Gs和Gq偶联受体调控。本文证明TREK-1可作为参与痛觉感知的分子传感器之一。TREK-1在小感觉神经元中高表达,存在于肽能和非肽能神经元中,并与辣椒素激活的非选择性离子通道TRPV1广泛共定位。TREK-1基因缺失的小鼠对接近有害热和疼痛热阈值的疼痛热感觉更敏感。这种表型与初级感觉神经元有关,因为在单纤维实验中发现多模式C纤维对热更敏感。基因敲除动物对低阈值机械刺激更敏感,在炎症条件下表现出热和机械性痛觉过敏增加。它们对渗透压变化引起的疼痛反应大幅降低,尤其是在前列腺素E2致敏的动物中。TREK-1似乎是多模式痛觉感知的重要离子通道,也是开发新型镇痛药的有吸引力的靶点。