An increased extrasynaptic NMDA tone inhibits A-type K+ current and increases excitability of hypothalamic neurosecretory neurons in hypertensive rats.
An increased extrasynaptic NMDA tone inhibits A-type K+ current and increases excitability of hypothalamic neurosecretory neurons in hypertensive rats.
复制标题
突触外 NMDA 张力的增加会抑制 A 型 K 电流并增加高血压大鼠下丘脑神经分泌神经元的兴奋性。
DOI：
10.1113/jp274327
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发表时间：
2017
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：
Zhang,Meng;Biancardi,ViniciaC;Stern,JavierE
关键点突触外NMDA受体（eNMDAR）和A型K+电流（IA）之间的功能偶联影响大细胞神经分泌细胞（MNCs）对生理挑战的稳态放电反应。然而，在疾病状态下，改变的eNMDAR-IA偶联是否也有助于加剧MNC活性和神经体液激活尚不清楚。我们表明，外源性应用NMDA激活eNMDAR抑制了来自假手术的MNC中的IA，但在来自肾血管性高血压（RVH）大鼠的MNC中没有。在RVH大鼠中，外源性诱发的NMDA电流的大小和NMDAR亚基的表达都没有改变。相反，我们发现，一个大的产生性谷氨酸张力，这不是由于谷氨酸转运活动的钝化，导致持续激活的eNMDAR，紧张性抑制IA，我们的研究表明，内源性谷氨酸对eNMDARs的激活加剧了RVH大鼠对IA的紧张性抑制，增强了MNC的兴奋性。突触外NMDA受体（eNMDAR）和A型K+电流（IA）之间的功能偶联影响下丘脑大细胞神经分泌神经元（MNCs）的放电活动，以及对生理挑战的稳态适应性反应。在这里，我们旨在确定eNMDAR-IAcoupling的变化是否也有助于疾病状态期间MNC活性的加剧。我们在假手术和肾血管性高血压（RVH）大鼠的MNC中联合使用了膜片钳电生理学和真实的时间PCR。外源性NMDA激活eNMDARs可抑制假手术大鼠的IA，但这种作用在RVH大鼠中很大程度上被减弱。反应迟钝不是由于eNMDAR表达和/或功能的变化，因为RVH大鼠中NMDA电流大小或逆转电位以及NR 1-NR 2A-D亚基表达水平均未改变。相反，我们发现了一个更大的内源性谷氨酸张力，导致持续激活的eNMDAR，紧张性抑制IA，也有助于更高的持续放电活动在RVH大鼠。RVH大鼠内源性谷氨酸张力的增强不是由于谷氨酸转运体活性的钝化。相反，观察到更高的转运蛋白活性，这可能是面对内源性张力升高的一种代偿机制。总之，我们的研究表明，升高的内源性谷氨酸张力导致eNMDAR的激活加剧，这反过来又有助于降低IA幅度和增加高血压大鼠MNCs的放电活动。
Key pointsA functional coupling between extrasynaptic NMDA receptors (eNMDARs) and the A‐type K+current (IA) influences homeostatic firing responses of magnocellular neurosecretory cells (MNCs) to a physiological challenge. However, whether an altered eNMDAR–IAcoupling also contributes to exacerbated MNC activity and neurohumoral activation during disease states is unknown.We show that activation of eNMDARs byexogenouslyapplied NMDA inhibitedIAin MNCs obtained from sham, but not in MNCs from renovascular hypertensive (RVH) rats.Neither the magnitude of the exogenously evoked NMDA current nor the expression of NMDAR subunits were altered in RVH rats.Conversely, we found that a largerendogenousglutamate tone, which was not due to blunted glutamate transport activity, led to the sustained activation of eNMDARs that tonically inhibitedIA, contributing in turn to higher firing activity in RVH rats.Our studies show that exacerbated activation of eNMDARs by endogenous glutamate contributes to tonic inhibition ofIAand enhanced MNC excitability in RVH rats.AbstractWe recently showed that a functional coupling between extrasynaptic NMDA receptors (eNMDARs) and the A‐type K+current (IA) influences the firing activity of hypothalamic magnocellular neurosecretory neurons (MNCs), as well as homeostatic adaptive responses to a physiological challenge. Here, we aimed to determine whether changes in the eNMDAR–IAcoupling also contributed to exacerbated MNC activity during disease states. We used a combination of patch‐clamp electrophysiology and real‐time PCR in MNCs in sham and renovascular hypertensive (RVH) rats. Activation of eNMDARs by exogenously applied NMDA inhibitedIAin sham rats, but this effect was largely blunted in RVH rats. The blunted response was not due to changes in eNMDAR expression and/or function, since neither NMDA current magnitude or reversal potential, nor the levels of NR1‐NR2A–D subunit expression were altered in RVH rats. Conversely, we found a larger endogenous glutamate tone, resulting in the sustained activation of eNMDARs that tonically inhibitedIAand contributed also to higher ongoing firing activity in RVH rats. The enhanced endogenous glutamate tone in RVH rats was not due to blunted glutamate transporter activity. Rather, a higher transporter activity was observed, which possibly acted as a compensatory mechanism in the face of the elevated endogenous tone. In summary, our studies indicate that an elevated endogenous glutamate tone results in an exacerbated activation of eNMDARs, which in turn contributes to diminishedIAmagnitude and increased firing activity of MNCs from hypertensive rats.