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Inhibition of the MAPK/ERK cascade: a potential transcription-dependent mechanism for the amnesic effect of anesthetic propofol

MAPK/ERK 的抑制作用: 丙泊酚导致失忆的一个可能的转录依赖性机制

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Abstract

Intravenous anesthetics are known to cause amnesia, but the underlying molecular mechanisms remain elusive. To identify a possible molecular mechanism, we recently turned our attention to a key intracellular signaling pathway organized by a family of mitogen-activated protein kinases (MAPKs). As a prominent synapse-to-nucleus superhighway, MAPKs couple surface glutamate receptors to nuclear transcriptional events essential for the development and/or maintenance of different forms of synaptic plasticity (long-term potentiation and long-term depression) and memory formation. To define the role of MAPK-dependent transcription in the amnesic property of anesthetics, we conducted a series of studies to examine the effect of a prototype intravenous anesthetic propofol on the MAPK response to N-methyl-Daspartate receptor (NMDAR) stimulation in hippocampal neurons. Our results suggest that propofol possesses the ability to inhibit NMDAR-mediated activation of a classic subclass of MAPKs, extracellular signal-regulated protein kinase 1/2 (ERK1/2). Concurrent inhibition of transcriptional activity also occurs as a result of inhibited responses of ERK1/2 to NMDA. These findings provide first evidence for an inhibitory modulation of the NMDAR-MAPK pathway by an intravenous anesthetic and introduce a new avenue to elucidate a transcription-dependent mechanism processing the amnesic effect of anesthetics.

摘要

静脉麻醉剂可引起失忆, 但其潜在的分子机制尚未阐明。 最近, 为了确定其可能的分子机制, 我们将注意力转向一条关键的细胞内信号通路, 即丝裂原活化蛋白激酶(MAPKs)信号通路。 各种类型的突触塑型(长时程增强和长时程抑制)及记忆的形成和保持均离不开核内的转录事件。作为一条重要的突触至神经核的信号通路, MAPKs将细胞表面的谷氨酸受体与细胞核内的转录事件联系在一起。为确定MAPK依赖的转录事件在麻醉剂致失忆特性中的作用, 我们在海马神经元细胞中做了一系列研究以检测静脉麻醉剂丙泊酚可否改变MAPK对N-甲基-D-天门冬氨酸受体(NMDAR)信号的反应。结果提示丙泊酚可以抑制NMDAR激活经典MAPKs: 胞外信号调节蛋白激酶 1/2 (ERK1/2)。 丙泊酚抑制ERK1/2激活的同时还降低其转录活性。这些结果证明了 NMDAR-MAPK 通路可受静脉麻醉剂的抑制, 此为麻醉剂致失忆效应的研究从转录机制上开辟了一条新途径。

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  1. Department of Anesthesiology, University of Missouri-Kansas City School of Medicine, Saint Luke’s Hospital, Kansas City, Missouri, 64108, USA

    Eugene E. Fibuch & John Q. Wang

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  1. Eugene E. Fibuch
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  2. John Q. Wang
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Correspondence to John Q. Wang.

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Fibuch, E.E., Wang, J.Q. Inhibition of the MAPK/ERK cascade: a potential transcription-dependent mechanism for the amnesic effect of anesthetic propofol. Neurosci. Bull. 23, 119–124 (2007). https://doi.org/10.1007/s12264-007-0017-y

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