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非超极化 GABAB 受体激活通过 cAMP/LKB1 调节神经元迁移和突起生长及定向。

Non-hyperpolarizing GABAB receptor activation regulates neuronal migration and neurite growth and specification by cAMP/LKB1.

机构信息

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego, 30 Genoa 16163, Italy.

出版信息

Nat Commun. 2013;4:1800. doi: 10.1038/ncomms2820.

Abstract

γ-Aminobutyric acid is the principal inhibitory neurotransmitter in adults, acting through ionotropic chloride-permeable GABAA receptors (GABAARs), and metabotropic GABABRs coupled to calcium or potassium channels, and cyclic AMP signalling. During early development, γ-aminobutyric acid is the main neurotransmitter and is not hyperpolarizing, as GABAAR activation is depolarizing while GABABRs lack coupling to potassium channels. Despite extensive knowledge on GABAARs as key factors in neuronal development, the role of GABABRs remains unclear. Here we address GABABR function during rat cortical development by in utero knockdown (short interfering RNA) of GABABR in pyramidal-neuron progenitors. GABABR short interfering RNA impairs neuronal migration and axon/dendrite morphological maturation by disrupting cyclic AMP signalling. Furthermore, GABABR activation reduces cyclic AMP-dependent phosphorylation of LKB1, a kinase involved in neuronal polarization, and rescues LKB1 overexpression-induced defects in cortical development. Thus, non-hyperpolarizing activation of GABABRs during development promotes neuronal migration and morphological maturation by cyclic AMP/LKB1 signalling.

摘要

γ-氨基丁酸是成人主要的抑制性神经递质,通过离子型氯离子可渗透的 GABA A 受体 (GABAAR) 和代谢型 GABA B 受体与钙或钾通道以及环 AMP 信号转导起作用。在早期发育过程中,γ-氨基丁酸是主要的神经递质,不会超极化,因为 GABAAR 的激活是去极化的,而 GABA B 受体缺乏与钾通道的偶联。尽管 GABAAR 作为神经元发育的关键因素已有广泛的了解,但 GABA B 受体的作用仍不清楚。在这里,我们通过在锥体神经元祖细胞中进行 GABA B 受体的体内敲低(短发夹 RNA)来解决大鼠皮质发育过程中的 GABA B 受体功能问题。GABA B 受体短发夹 RNA 通过破坏环 AMP 信号转导来损害神经元迁移和轴突/树突形态成熟。此外,GABA B 受体的激活减少了参与神经元极化的激酶 LKB1 的环 AMP 依赖性磷酸化,并且挽救了 LKB1 过表达诱导的皮质发育缺陷。因此,发育过程中非超极化激活的 GABA B 受体通过环 AMP/LKB1 信号促进神经元迁移和形态成熟。

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