Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei, China.
J Physiol. 2018 Sep;596(17):4269-4283. doi: 10.1113/JP276394. Epub 2018 Jul 30.
α2δ-1 is upregulated, promoting the interaction with NMDA receptors (NMDARs), in the hypothalamus in a rat model of hypertension. The prevalence of α2δ-1-bound NMDARs at synaptic sites in the hypothalamus is increased in hypertensive animals. α2δ-1 is essential for the increased presynaptic and postsynaptic NMDAR activity of hypothalamic neurons in hypertension. α2δ-1-bound NMDARs in the hypothalamus are critically involved in augmented sympathetic outflow in hypertensive animals.
Increased glutamate NMDA receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus leads to augmented sympathetic outflow in hypertension. However, the molecular mechanisms underlying this effect remain unclear. α2δ-1, previously considered to be a voltage-activated calcium channel subunit, is a newly discovered powerful regulator of NMDARs. In the present study, we determined the role of α2δ-1 in regulating synaptic NMDAR activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons in spontaneously hypertensive rats (SHRs). We show that the protein levels of α2δ-1 and NMDARs in synaptosomes and the α2δ-1-NMDAR complexes in the hypothalamus were substantially higher in SHRs than in normotensive control rats. The basal amplitude of evoked NMDAR currents and NMDAR-mediated synaptic glutamate release in RVLM-projecting PVN neurons were significantly increased in SHRs. Strikingly, inhibiting α2δ-1 activity with gabapentin or disrupting the α2δ-1-NMDAR association with an α2δ-1 C-terminus peptide completely normalized the amplitude of evoked NMDAR currents and NMDAR-mediated synaptic glutamate release in RVLM-projecting PVN neurons in SHRs. In addition, microinjection of the α2δ-1 C-terminus peptide into the PVN substantially reduced arterial blood pressure and renal sympathetic nerve discharges in SHRs. Our findings indicate that α2δ-1-bound NMDARs in the PVN are required for the potentiated presynaptic and postsynaptic NMDAR activity of PVN presympathetic neurons and for the elevated sympathetic outflow in hypertension. α2δ-1-bound NMDARs may be an opportune target for treating neurogenic hypertension.
在高血压大鼠模型中，α2δ-1 上调，促进其与 NMDA 受体（NMDAR）相互作用。高血压动物下丘脑突触部位与 α2δ-1 结合的 NMDAR 增多。α2δ-1 是高血压时下丘脑神经元突触前和突触后 NMDAR 活性增加所必需的。与 α2δ-1 结合的 NMDAR 参与高血压动物交感神经输出的增加。
下丘脑室旁核（PVN）中谷氨酸 NMDA 受体（NMDAR）活性增加导致高血压时交感神经输出增加。然而，这种作用的分子机制尚不清楚。α2δ-1 先前被认为是电压门控钙通道亚基，是一种新发现的 NMDAR 强有力的调节剂。在本研究中，我们确定了 α2δ-1 在调节自发性高血压大鼠（SHR）中 RVLM 投射 PVN 神经元突触 NMDAR 活性中的作用。我们发现，与正常血压对照大鼠相比，SHR 突触体中的 α2δ-1 和 NMDAR 蛋白水平以及下丘脑的 α2δ-1-NMDAR 复合物显著升高。SHR 中 RVLM 投射 PVN 神经元诱发的 NMDAR 电流和 NMDAR 介导的突触谷氨酸释放的基础振幅显著增加。引人注目的是，用加巴喷丁抑制 α2δ-1 活性或用 α2δ-1 C 端肽破坏 α2δ-1-NMDAR 结合，可完全使 SHR 中 RVLM 投射 PVN 神经元诱发的 NMDAR 电流和 NMDAR 介导的突触谷氨酸释放的振幅正常化。此外，将 α2δ-1 C 端肽微注射到 PVN 中可显著降低 SHR 的动脉血压和肾交感神经放电。我们的研究结果表明，PVN 中的 α2δ-1 结合的 NMDAR 对于 PVN 前交感神经元的增强的突触前和突触后 NMDAR 活性以及高血压时升高的交感神经输出是必需的。与 α2δ-1 结合的 NMDAR 可能是治疗神经原性高血压的一个合适靶点。
