Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue

Guillaume Sandoz; Dominique Douguet; Franck Chatelain; Michel Lazdunski; Florian Lesage

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Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue

机译：细胞外酸化通过一个保守的组氨酸残基对TREK1和TREK2钾通道产生相反的作用

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摘要

Mechanosensitive K~+ channels TREK1 and TREK2 form a subclass of two P-domain K~+ channels. They are potently activated by poly-unsaturated fatty acids and are involved in neuroprotection, anesthesia, and pain perception. Here, we show that acidification of the extracellular medium strongly inhibits TREK1 with an apparent pK near to 7.4 corresponding to the physiological pH. The all-or-none effect of pH variation is steep and is observed within one pH unit. TREK2 is not inhibited but activated by acidification within the same range of pH, despite its close homology with TREK1. A single conserved residue, H126 in TREK1 and H151 in TREK2, is involved in proton sensing. This histidine is located in the M1P1 extracellular loop preceding the first P domain. The differential effect of acidification, that is, activation for TREK2 and inhibition for TREK1, involves other residues located in the P2M4 loop, linking the second P domain and the fourth membrane-spanning segment. Structural modeling of TREK1 and TREK2 and site-directed mu-tagenesis strongly suggest that attraction or repulsion between the protonated side chain of histidine and closely located negatively or positively charged residues in P2M4 control outer gating of these channels. The differential sensitivity of TREK1 and TREK2 to external pH variations discriminates between these two K~+ channels that otherwise share the same regulations by physical and chemical stimuli, and by hormones and neurotransmitters.

机译：机械敏感的K〜+通道TREK1和TREK2形成两个P域K〜+通道的子类。它们被多不饱和脂肪酸有效激活，并参与神经保护，麻醉和疼痛感。在这里，我们表明，细胞外介质的酸化强烈抑制TREK1，其表观pK接近7.4，对应于生理pH。 pH变化的全有或无影响是陡峭的，并且在一个pH单位内可以观察到。尽管TREK2与TREK1具有紧密的同源性，但在相同的pH范围内，它不会被酸化抑制，但会被酸化激活。单个保守残基，TREK1中的H126和TREK2中的H151，涉及质子传感。该组氨酸位于第一个P结构域之前的M1P1细胞外环中。酸化的不同作用，即激活TREK2和抑制TREK1，涉及位于P2M4环中的其他残基，连接第二个P结构域和第四个跨膜片段。 TREK1和TREK2的结构模型以及定点诱变强烈表明，组氨酸的质子化侧链与P2M4中带负电或正电荷的残基之间的吸引或排斥作用控制着这些通道的外部门控。 TREK1和TREK2对外部pH值变化的差异敏感性区分了这两个K〜+通道，这些通道在物理和化学刺激以及激素和神经递质方面均具有相同的调节。

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2009年第34期|14628-14633|共6页
作者
Guillaume Sandoz; Dominique Douguet; Franck Chatelain; Michel Lazdunski; Florian Lesage;
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作者单位

Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6097, Universite de Nice Sophia-Antipolis, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France;

Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6097, Universite de Nice Sophia-Antipolis, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France;

Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6097, Universite de Nice Sophia-Antipolis, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France;

Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6097, Universite de Nice Sophia-Antipolis, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France;

Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6097, Universite de Nice Sophia-Antipolis, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
ion channel; mutagenesis; structural modeling;

机译：离子通道诱变;结构建模;

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2. How ion channels sense mechanical force: insights from mechanosensitiven K2P channels TRAAK, TREK1, and TREK2 [J] . Brohawn Stephen G. Annals of the New York Academy of Sciences . 2015,第期

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6. Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue [O] . Guillaume Sandoz, Dominique Douguet, Franck Chatelain, 2009

机译：细胞外酸化通过一个保守的组氨酸残基对TREK1和TREK2钾通道产生相反的作用
7. Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue. [O] . Sandoz, Guillaume, Douguet, Dominique, Chatelain, Franck, 2009

机译：细胞外酸化通过单个保守的组氨酸残基对TREK1和TREK2钾通道施加相反的作用。

Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue

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