Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures.
Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures.
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DOI：
10.1016/j.nbd.2014.12.020
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发表时间：
2015-09
影响因子：
6.1
通讯作者：
Hershfinkel, Michal
中科院分区：
文献类型：
--
作者：
Gilad, David;Shorer, Sharon;Ketzef, Maya;Friedman, Alon;Sekler, Israel;Aizenman, Elias;Hershfinkel, Michal
本研究的目的是探讨突触代谢型锌受体mZnR/GPR 39在癫痫发作的生理适应中的作用。我们先前证明，mZnR/GPR 39的突触激活通过上调神经元K+/Cl−协同转运蛋白2（KCC 2）活性增强海马中的抑制驱动。在这里，我们首先表明，mZnR/GPR 39敲除（KO）成年小鼠有显着增强的易感性癫痫发作引发的一个单一的腹腔注射红藻氨酸，相比野生型（WT）的同窝仔。红藻氨酸盐还显著增强幼年mZnR/GPR 39 KO海马切片中的海马相关γ振荡活性，这是一种可以通过细胞外Zn 2+螯合在WT组织中再现的现象。重要的是，红藻氨酸诱导的突触Zn 2+释放增强WT中KCC 2的表面表达和转运活性，但不增强mZnR/GPR 39 KO海马神经元。KCC 2的红藻氨酸依赖性上调需要mZnR/GPR 39激活Gαq/磷脂酶C/细胞外调节激酶（ERK 1/2）信号级联。我们认为，mZnR/GPR 39依赖上调KCC 2活性提供稳态适应兴奋性刺激，通过增加抑制。因此，mZnR/GPR 39可以提供用于抑制癫痫发作活性的新的药理学靶标。
The aim of this study was to investigate the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. We previously demonstrated that synaptic activation of mZnR/GPR39 enhances inhibitory drive in the hippocampus by upregulating neuronal K+/Cl− co-transporter 2 (KCC2) activity. Here, we first show that mZnR/GPR39 knockout (KO) adult mice have dramatically enhanced susceptibility to seizures triggered by a single intraperitoneal injection of kainic acid, when compared to wild type (WT) littermates. Kainate also substantially enhances seizure-associated gamma oscillatory activity in juvenile mZnR/GPR39 KO hippocampal slices, a phenomenon that can be reproduced in WT tissue by extracellular Zn2+ chelation. Importantly, kainate-induced synaptic Zn2+ release enhances surface expression and transport activity of KCC2 in WT, but not mZnR/GPR39 KO hippocampal neurons. Kainate-dependent upregulation of KCC2 requires mZnR/GPR39 activation of the Gαq/phospholipase C/extracellular regulated kinase (ERK1/2) signaling cascade. We suggest that mZnR/GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition. As such, mZnR/GPR39 may provide a novel pharmacological target for dampening epileptic seizure activity.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
16.2
作者：
Huang, Yang Z.;Pan, Enhui;McNamara, James O.
通讯作者：
McNamara, James O.
通过MZNR/GPR39受体对KCC2活性的上调。
DOI：
10.1523/jneurosci.2205-11.2011
发表时间：
2011-09-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chorin E;Vinograd O;Fleidervish I;Gilad D;Herrmann S;Sekler I;Aizenman E;Hershfinkel M
通讯作者：
Hershfinkel M
影响因子：
1.6
作者：
Ganesh, R.;Janakiraman, Lalitha
通讯作者：
Janakiraman, Lalitha
DOI：
10.1073/pnas.201193398
发表时间：
2001-09-25
影响因子：
11.1
作者：
Hershfinkel, M;Moran, A;Sekler, I
通讯作者：
Sekler, I