A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity.
A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity.
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突触外 NMDA 受体与星形胶质细胞控制下的 A 型 K 通道之间的功能耦合可调节下丘脑神经分泌神经元活动。
DOI：
10.1113/jphysiol.2014.270793
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Stern,JavierE
中科院分区：
文献类型：
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作者：
Naskar,Krishna;Stern,JavierE
关键点在下丘脑大细胞神经分泌细胞中，谷氨酸NMDA受体的激活导致瞬时电压门控A型K+电流（IA）的抑制，这是一种钙离子和蛋白激酶C依赖的方式。负性NMDAR-IA功能偶联涉及突触外（e）NMDARs的激活。eNMDAR-IAcoupling由内源性细胞外谷氨酸参与，其水平由星形胶质细胞谷氨酸GLT 1转运蛋白控制。eNMDAR-IAcoupling在脱水过程中增强，星形胶质细胞GLT 1效率减弱的情况。eNMDAR-IAcoupling导致大细胞神经分泌神经元的神经元兴奋性和放电活动增加。总之，这些研究支持eNMDAR-IAcoupling的概念。IAcoupling是一个强大的机制，谷氨酸增加大细胞神经分泌兴奋性和firing activity.AbstractNeuronal活动是由内在属性和外在突触输入之间的微调平衡控制。此外，邻近的星形胶质细胞现在被认为影响广泛的神经元功能。然而，这三个关键因素如何协调一致地调节和微调神经元输出还没有很好地理解。在这里，我们发现在大鼠下丘脑大细胞神经分泌细胞（MNCs）中，谷氨酸NMDA受体（NMDAR）与瞬时电压门控A型K+电流（IA）负耦合。我们发现，激活NMDAR的细胞外谷氨酸水平的影响，星形胶质细胞谷氨酸转运导致了显着抑制IA。NMDAR-IA功能偶联由突触外NMDARs的激活引起，是钙和蛋白激酶C依赖性的，并涉及IA的增强的稳态电压依赖性失活。NMDAR-IAcoupling可缩短膜去极化引起的第一个诱发电位的潜伏期，增加诱发动作电位的总数，从而增强神经元的输入/输出功能。最后，我们发现在脱水大鼠中NMDA介导的IA抑制作用减弱。总之，我们的研究结果支持了一种新的信号传导机制，该机制涉及突触外NMDAR和A型K+通道之间的功能耦合，这受到局部星形胶质细胞的影响。我们表明，这种信号复合物在调节下丘脑神经元兴奋性中发挥重要作用，这可能有助于在持续的渗透压挑战，如脱水过程中的适应性反应。
Key pointsIn hypothalamic magnocellular neurosecretory cells, activation of glutamate NMDA receptors leads to inhibition of the transient voltage‐gated A‐type K+current (IA), in a Ca2+‐ and protein kinase C‐dependent manner.The negative NMDAR–IAfunctional coupling involves activation of extrasynaptic (e)NMDARs. The eNMDAR–IAcoupling is engaged by endogenous extracellular glutamate, whose levels are controlled by astrocyte glutamate GLT1 transporters.The eNMDAR–IAcoupling is enhanced during dehydration, a condition in which astrocyte GLT1 efficiency is blunted.The eNMDAR–IAcoupling results in increased neuronal excitability and firing activity in magnocellular neurosecretory neurons.Taken together these studies support the concept that the eNMDAR–IAcoupling is a powerful mechanism by which glutamate increases magnocellular neurosecretory excitability and firing activity.AbstractNeuronal activity is controlled by a fine‐tuned balance between intrinsic properties and extrinsic synaptic inputs. Moreover, neighbouring astrocytes are now recognized to influence a wide spectrum of neuronal functions. Yet, how these three key factors act in concert to modulate and fine‐tune neuronal output is not well understood. Here, we show that in rat hypothalamic magnocellular neurosecretory cells (MNCs), glutamate NMDA receptors (NMDARs) are negatively coupled to the transient, voltage‐gated A‐type K+current (IA). We found that activation of NMDARs by extracellular glutamate levels influenced by astrocyte glutamate transporters resulted in a significant inhibition ofIA. The NMDAR–IAfunctional coupling resulted from activation of extrasynaptic NMDARs, was calcium‐ and protein kinase C‐dependent, and involved enhanced steady‐state, voltage‐dependent inactivation ofIA. The NMDAR–IAcoupling diminished the latency to the first evoked spike in response to membrane depolarization and increased the total number of evoked action potentials, thus strengthening the neuronal input/output function. Finally, we found a blunted NMDA‐mediated inhibition ofIAin dehydrated rats. Together, our findings support a novel signalling mechanism that involves a functional coupling between extrasynaptic NMDARs and A‐type K+channels, which is influenced by local astrocytes. We show this signalling complex to play an important role in modulating hypothalamic neuronal excitability, which may contribute to adaptive responses during a sustained osmotic challenge such as dehydration.