Zhang Meng, Biancardi Vinicia C, Stern Javier E
Department of Physiology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
J Physiol. 2017 Jul 15;595(14):4647-4661. doi: 10.1113/JP274327. Epub 2017 May 23.
A functional coupling between extrasynaptic NMDA receptors (eNMDARs) and the A-type K current (I ) influences homeostatic firing responses of magnocellular neurosecretory cells (MNCs) to a physiological challenge. However, whether an altered eNMDAR-I coupling also contributes to exacerbated MNC activity and neurohumoral activation during disease states is unknown. We show that activation of eNMDARs by exogenously applied NMDA inhibited I in 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 larger endogenous glutamate tone, which was not due to blunted glutamate transport activity, led to the sustained activation of eNMDARs that tonically inhibited I , 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 of I and enhanced MNC excitability in RVH rats.
We recently showed that a functional coupling between extrasynaptic NMDA receptors (eNMDARs) and the A-type K current (I ) 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-I coupling 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 inhibited I in 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 inhibited I and 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 diminished I magnitude and increased firing activity of MNCs from hypertensive rats.
突触外N-甲基-D-天冬氨酸受体（eNMDARs）与A型钾电流（I）之间的功能性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，eNMDAR-I偶联的改变是否也会导致MNC活性加剧和神经体液激活尚不清楚。我们发现，外源性应用NMDA激活eNMDARs可抑制假手术组大鼠MNCs中的I，但对肾血管性高血压（RVH）大鼠的MNCs则无此作用。RVH大鼠中外源性诱发的NMDA电流幅度和NMDAR亚基的表达均未改变。相反，我们发现内源性谷氨酸水平升高（并非由于谷氨酸转运活性减弱）导致eNMDARs持续激活，从而持续抑制I，进而导致RVH大鼠的放电活性更高。我们的研究表明，内源性谷氨酸导致的eNMDARs激活加剧，导致I的持续性抑制，并增强了RVH大鼠MNCs的兴奋性。
我们最近发现，突触外N-甲基-D-天冬氨酸受体（eNMDARs）与A型钾电流（I）之间的功能性偶联影响下丘脑大细胞神经分泌神经元（MNCs）的放电活性，以及对生理挑战的稳态适应性反应。在此，我们旨在确定eNMDAR-I偶联的变化是否也会导致疾病状态下MNC活性加剧。我们对假手术组和肾血管性高血压（RVH）大鼠的MNCs进行了膜片钳电生理学和实时PCR相结合的实验。外源性应用NMDA激活eNMDARs可抑制假手术组大鼠的I，但在RVH大鼠中这种作用基本消失。这种减弱的反应并非由于eNMDAR表达和/或功能的改变，因为RVH大鼠的NMDA电流幅度、反转电位以及NR1-NR2A-D亚基的表达水平均未改变。相反，我们发现内源性谷氨酸水平升高，导致eNMDARs持续激活，从而持续抑制I，并导致RVH大鼠的基础放电活性更高。RVH大鼠内源性谷氨酸水平升高并非由于谷氨酸转运体活性减弱。相反，观察到更高的转运体活性，这可能是面对内源性谷氨酸水平升高时的一种代偿机制。总之，我们的研究表明，内源性谷氨酸水平升高导致eNMDARs激活加剧，进而导致I幅度减小，高血压大鼠MNCs的放电活性增加。
