Glucocorticoids modulate neural activity via a rapid non-genomic effect on Kv2.2 channels in the central nervous system.
Glucocorticoids modulate neural activity via a rapid non-genomic effect on Kv2.2 channels in the central nervous system.
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DOI：
10.1016/j.ynstr.2023.100593
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发表时间：
2024-01
影响因子：
5
通讯作者：
Hu, Changlong
中科院分区：
文献类型：
--
作者：
Wang, Yuqi;Zhang, Yuchen;Hu, Jiawei;Pan, Chengfang;Gao, Yiming;Liu, Qingzhuo;Xu, Wendong;Xue, Lei;Hu, Changlong
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对神经元产生影响。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细胞和急性脑片上Kv2.2通道的快速非基因组效应，包括脑干中的皮质锥体神经元和帽状突触。我们发现，内源性糖皮质激素皮质醇通过激活膜相关的糖皮质激素受体，增加表达Kv2.2的HEK293细胞的单通道开放概率，从而迅速增加Kv2.2电流。糖皮质激素受体的膜不通透性激动剂--牛血清白蛋白偶联地塞米松可模拟皮质醇对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激酶而诱导的，ERK信号通路的拮抗剂U0126可以抑制这种激活。在第二层皮质锥体神经元和被夹持的突触的胞体中，皮质醇通过激活Kv2.2通道抑制动作电位在去极化时的放电频率，并降低高频刺激的成功率。我们进一步研究了突触后的反应，发现皮质醇不影响mEPSC和诱发的EPSC，但增加了高频刺激序列诱导的活动依赖性突触抑制。综上所述，糖皮质激素可通过ERK1/2信号通路，通过膜相关糖皮质激素受体快速激活Kv2.2通道，抑制突触前动作电位的激活，抑制突触传递和可塑性。这可能是糖皮质激素引起中枢神经系统非基因组效应的普遍机制。
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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影响因子：
2.5
作者：
Boudaba, C;Schrader, LA;Tasker, JG
通讯作者：
Tasker, JG
影响因子：
2.5
作者：
Hermanstyne, Tracey O.;Kihira, Yoshitaka;Misono, Kaori;Deitchler, Ashley;Yanagawa, Yuchio;Misonou, Hiroaki
通讯作者：
Misonou, Hiroaki
影响因子：
4
作者：
Fahmi, AI;Forhead, AJ;Vandenberg, JI
通讯作者：
Vandenberg, JI
DOI：
10.1523/jneurosci.0496-11.2011
发表时间：
2011-07-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hill MN;McLaughlin RJ;Pan B;Fitzgerald ML;Roberts CJ;Lee TT;Karatsoreos IN;Mackie K;Viau V;Pickel VM;McEwen BS;Liu QS;Gorzalka BB;Hillard CJ
通讯作者：
Hillard CJ
影响因子：
3.7
作者：
Boyle, N. B.;Lawton, C.;Dye, L.
通讯作者：
Dye, L.