Department of Physiology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA.
J Physiol. 2017 Dec 15;595(24):7399-7411. doi: 10.1113/JP275169. Epub 2017 Nov 15.
NMDA receptor (NMDAR)-mediated Ca signalling plays a critical role in modulating hypothalamic neurosecretory function. However, whether an altered NMDAR-evoked changes in Ca (NMDAR-ΔCa ) signalling in magnocellular neurosecretory cells (MNCs) may contribute to neurohumoral activation during disease states is unknown. We show that activation of NMDARs evoked similar inward currents in MNCs of sham and renovascular hypertensive (RVH) rats. Despite this, a prolonged and larger NMDAR-ΔCa response was observed in the latter. The exacerbated NMDAR-ΔCa responses in MNCs of RVH rats affected both somatic and dendritic compartments. Inhibition of the endoplasmic reticulum sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump prolonged NMDAR-ΔCa responses in sham rats, but not in RVH rats. Our study supports an altered spatiotemporal dynamic of NMDAR-ΔCa signalling in MNCs from RVH rats, partly due to blunted endoplasmic reticulum Ca buffering capacity.
A growing body of evidence supports an elevated NMDA receptor (NMDAR)-mediated glutamate excitatory function in the supraoptic nucleus and paraventricular nucleus of hypertensive rats that contributes to neurohumoral activation in this disease. However, the precise mechanisms underlying altered NMDAR signalling in hypertension remain to be elucidated. In this study, we performed simultaneous electrophysiology and fast confocal Ca imaging to determine whether altered NMDAR-mediated changes in intracellular Ca levels (NMDAR-ΔCa ) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in renovascular hypertensive (RVH) rats. We found that despite evoking a similar excitatory inward current, activation of NMDARs resulted in a larger and prolonged ΔCa in MNCs from RVH rats. Changes in NMDAR-ΔCa dynamics were observed both in somatic and dendritic compartments. Inhibition of the sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump activity with thapsigargin prolonged NMDAR-ΔCa responses in MNCs of sham rats, but this effect was occluded in RVH rats, thus equalizing the magnitude and time course of the NMDA-ΔCa responses between the two experimental groups. Taken together, our results support (1) an exacerbated NMDAR-ΔCa response in somatodendritic compartments of MNCs of RVH rats, and (2) that a blunted ER Ca buffering capacity contributes to the altered NMDAR-ΔCa dynamics in this condition. Thus, altered spatiotemporal dynamics of the NMDAR-ΔCa response stands as an underlying mechanism contributing to neurohumoral activation in neurogenic hypertension.
N-甲基-D-天冬氨酸受体（NMDAR）介导的 Ca 信号在调节下丘脑神经分泌功能方面起着关键作用。然而，在疾病状态下，大细胞神经分泌细胞（MNC）中 NMDAR 诱发的 Ca 变化（NMDAR-ΔCa）信号是否会导致神经激素激活尚不清楚。我们发现，在假手术和肾血管性高血压（RVH）大鼠的 MNC 中，激活 NMDAR 可诱发相似的内向电流。尽管如此，后者观察到的 NMDAR-ΔCa 反应时间更长、幅度更大。RVH 大鼠 MNC 中 NMDAR-ΔCa 反应的加剧影响了体细胞和树突隔室。内质网肌浆网钙转运 ATP 酶（SERCA）泵的抑制延长了假手术大鼠的 NMDAR-ΔCa 反应，但对 RVH 大鼠没有影响。我们的研究支持 RVH 大鼠 MNC 中 NMDAR-ΔCa 信号的时空动态发生改变，部分原因是内质网 Ca 缓冲能力减弱。
越来越多的证据支持高血压大鼠的上核和室旁核中 NMDA 受体（NMDAR）介导的谷氨酸兴奋性功能升高，这有助于该疾病中的神经激素激活。然而，高血压中改变的 NMDAR 信号的具体机制仍有待阐明。在这项研究中，我们同时进行了电生理学和快速共聚焦 Ca 成像，以确定在肾血管性高血压（RVH）大鼠的下丘脑大细胞神经分泌细胞（MNC）中是否发生了改变的 NMDAR 介导的细胞内 Ca 水平变化（NMDAR-ΔCa）。我们发现，尽管激活 NMDAR 会引起相似的兴奋性内向电流，但在 RVH 大鼠的 MNC 中，NMDAR 的激活会导致更大和更长时间的 ΔCa。在体细胞和树突隔室中都观察到 NMDAR-ΔCa 动力学的变化。用 thapsigargin 抑制肌浆网钙转运 ATP 酶（SERCA）泵活性可延长 sham 大鼠 MNC 中的 NMDAR-ΔCa 反应，但在 RVH 大鼠中，这种作用被阻断，从而使两组实验之间的 NMDA-ΔCa 反应的幅度和时程相等。总之，我们的结果支持（1）RVH 大鼠 MNC 体细胞和树突隔室中 NMDAR-ΔCa 反应加剧，以及（2）内质网 Ca 缓冲能力减弱导致这种情况下改变的 NMDAR-ΔCa 动力学。因此，改变的 NMDAR-ΔCa 反应的时空动力学是导致神经源性高血压中神经激素激活的潜在机制。
