糖皮质激素通过对中枢神经系统Kv2.2通道的快速非基因组效应调节神经活动

IF 4.3 2区 医学 Q1 NEUROSCIENCES
Yuqi Wang , Yuchen Zhang , Jiawei Hu , Chengfang Pan , Yiming Gao , Qingzhuo Liu , Wendong Xu , Lei Xue , Changlong Hu
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引用次数: 0

摘要

糖皮质激素是主要的应激激素,通过基因组和非基因组信号通路发挥神经元作用。然而,它们对神经活动的快速非基因组效应和潜在机制仍然难以捉摸。在本研究中,我们研究了糖皮质激素对培养的HEK293细胞和包括皮质锥体神经元和脑干花萼型突触在内的急性脑切片中Kv2.2通道的快速非基因组效应。我们发现,内源性糖皮质激素皮质醇通过激活膜相关糖皮质激素受体,增加表达Kv2.2的HEK293细胞的单通道打开概率,从而迅速增加Kv2.2电流。牛血清白蛋白偶联地塞米松是一种糖皮质激素受体的膜不渗透性激动剂,可以模拟皮质醇对Kv2.2通道的作用。皮质醇增加的Kv2.2电流是通过激活细胞外信号调节蛋白激酶(ERK) 1/2激酶诱导的,该激酶可被ERK信号通路拮抗剂U0126抑制。在皮层第2层锥体神经元和Held突触的花萼中,皮质醇通过激活Kv2.2通道抑制去极化过程中的动作电位放电频率,降低高频刺激的成功率。我们进一步检查了突触后反应,发现皮质醇不影响mEPSC并诱发EPSC,但增加了高频刺激引起的活动依赖性突触抑制。综上所述,糖皮质激素可通过膜相关糖皮质激素受体通过ERK1/2信号通路快速激活Kv2.2通道,抑制突触前动作电位放电,抑制突触传递和可塑性。这可能是糖皮质激素诱导中枢神经系统非基因组效应的普遍机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Glucocorticoids modulate neural activity via a rapid non-genomic effect on Kv2.2 channels in the central nervous system

Glucocorticoids are primary stress hormones that exert neuronal effects via both genomic and non-genomic signaling pathways. However, their rapid non-genomic effects and underlying mechanisms on neural activities remain elusive. In the present study, we investigated the rapid non-genomic effect of glucocorticoids on Kv2.2 channels in cultured HEK293 cells and acute brain slices including cortical pyramidal neurons and calyx-type synapses in the brain stem. We found that cortisol, the endogenous glucocorticoids, rapidly increased Kv2.2 currents by increasing the single-channel open probability in Kv2.2-expressing HEK293 cells through activation of the membrane-associated glucocorticoid receptor. Bovine serum albumin-conjugated dexamethasone, a membrane-impermeable agonist of the glucocorticoid receptor, could mimic the effect of cortisol on Kv2.2 channels. The cortisol-increased Kv2.2 currents were induced by activation of the extracellular signal-regulated protein kinase (ERK) 1/2 kinase, which could be inhibited by U0126, an antagonist of the ERK signaling pathway. In layer 2 cortical pyramidal neurons and the calyx of Held synapses, cortisol suppressed the action potential firing frequency during depolarization and reduced the successful rate upon high-frequency stimulation by activating Kv2.2 channels. We further examined the postsynaptic responses and found that cortisol did not affect the mEPSC and evoked EPSC, but increased the activity-dependent synaptic depression induced by a high-frequency stimulus train. In conclusion, glucocorticoids can rapidly activate Kv2.2 channels through membrane-associated glucocorticoid receptors via the ERK1/2 signaling pathway, suppress presynaptic action potential firing, and inhibit synaptic transmission and plasticity. This may be a universal mechanism of the glucocorticoid-induced non-genomic effects in the central nervous system.

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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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