Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor.
Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor.
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通过MZNR/GPR39受体对KCC2活性的上调。
DOI：
10.1523/jneurosci.2205-11.2011
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发表时间：
2011-09-07
期刊：
影响因子：
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通讯作者：
Hershfinkel M
中科院分区：
文献类型：
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作者：
Chorin E;Vinograd O;Fleidervish I;Gilad D;Herrmann S;Sekler I;Aizenman E;Hershfinkel M
囊泡锌2+调节突触后神经元兴奋性后，其与谷氨酸的共同释放。我们以前证明，突触锌+的行为，通过一个独特的代谢型锌敏感受体（mZnR）在神经元中触发海马中的钙反应。在这里，我们表明，mZnR信号的生理激活诱导增强K+/Cl−协同转运蛋白2（KCC 2）的活性和表面表达。由于KCC 2是神经元中主要的Cl−外向转运体，因此Zn 2+也会引发GABAA逆转电位的显著超极化转变。苔藓纤维刺激依赖性KCC 2活性上调被消除在切片从Zn 2+转运蛋白3缺陷的动物，缺乏突触Zn 2+。重要的是，在缺乏G蛋白偶联受体GPR 39的小鼠切片中也不存在活性依赖性ZnR信号传导和随后的KCC 2活性增强，将该蛋白鉴定为功能性神经元mZnR。我们的工作阐明了突触释放的Zn 2+作为神经递质信号通过激活mZnR增加Cl−转运，从而增强突触后细胞的抑制性音调的根本重要作用。
Vesicular Zn2+ regulates postsynaptic neuronal excitability upon its corelease with glutamate. We previously demonstrated that synaptic Zn2+ acts via a distinct metabotropic zinc-sensing receptor (mZnR) in neurons to trigger Ca2+ responses in the hippocampus. Here, we show that physiological activation of mZnR signaling induces enhanced K+/Cl− cotransporter 2 (KCC2) activity and surface expression. As KCC2 is the major Cl− outward transporter in neurons, Zn2+ also triggers a pronounced hyperpolarizing shift in the GABAA reversal potential. Mossy fiber stimulation-dependent upregulation of KCC2 activity is eliminated in slices from Zn2+ transporter 3-deficient animals, which lack synaptic Zn2+. Importantly, activity-dependent ZnR signaling and subsequent enhancement of KCC2 activity are also absent in slices from mice lacking the G-protein-coupled receptor GPR39, identifying this protein as the functional neuronal mZnR. Our work elucidates a fundamentally important role for synaptically released Zn2+ acting as a neurotransmitter signal via activation of a mZnR to increase Cl− transport, thereby enhancing inhibitory tone in postsynaptic cells.