Brain α2δ-1-Bound NMDA Receptors Drive Calcineurin Inhibitor-Induced Hypertension.
Brain α2δ-1-Bound NMDA Receptors Drive Calcineurin Inhibitor-Induced Hypertension.
复制标题
脑α2β-1 结合NMDA 受体驱动钙调神经磷酸酶抑制剂诱发的高血压。
DOI：
10.1161/circresaha.123.322562
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发表时间：
2023
影响因子：
20.1
通讯作者：
Pan,Hui-Lin
中科院分区：
文献类型：
--
作者：
Zhou,Jing-Jing;Shao,Jian-Ying;Chen,Shao-Rui;Pan,Hui-Lin
钙调神经磷酸酶在免疫T细胞和神经系统中高度富集。钙调磷酸酶抑制剂，包括环孢素和他克莫司（FK 506），是保护移植器官和组织的免疫抑制方案的基石。然而，这些药物往往会导致持续性高血压，由于过量的交感神经流出，这是维持N-甲基-D-天冬氨酸受体（NMDAR）介导的兴奋性输入下丘脑室旁核（PVN）。目前尚不清楚钙调磷酸酶抑制剂如何增加PVN中的NMDAR活性以增强交感血管活性。α2δ-1（由Cacna 2d 1基因编码），俗称钙通道亚基，是一种新发现的NMDAR相互作用蛋白。在这项研究中，我们确定α2δ-1是否在钙调神经磷酸酶诱导的突触NMDAR高活性的PVN和高血压development. METHODS免疫印迹和免疫共沉淀法被用来定量突触蛋白水平和GluN 1（强制性NMDAR亚基）和α2δ-1之间的物理相互作用。在灌注脑切片中对逆行标记的脊髓投射PVN进行全细胞膜片钳记录，以测量突触前和突触后NMDAR活性。在啮齿类动物体内植入无线电遥测技术，连续记录清醒状态下的动脉血压。长期给予大鼠FK 506可显著增加PVN突触体中α2δ-1、GluN 1和α2δ-1-GluN 1复合物的蛋白水平。这些作用通过用加巴喷丁抑制α2δ-1或用α2δ-1 C-末端肽中断α2 δ-1-NMDAR相互作用来阻断。FK 506处理增强了脊髓投射PVN神经元中突触前和突触后NMDAR的活性;加巴喷丁、Cacna 2d 1敲除或α2δ-1 C末端肽消除了这种作用。此外，向PVN微量注射α2δ-1 C-末端肽可减少肾交感神经放电和FK 506处理后升高的动脉血压。值得注意的是，加巴喷丁的同时给药可预防大鼠发生FK 506诱导的高血压。结论α2δ-1在钙调神经磷酸酶介导的室旁核前交感神经元突触NMDAR活性增加和交感神经流出中起重要作用。因此，α2δ-1和α2δ-1结合的NMDAR代表了治疗钙调磷酸酶介导的高血压的新靶点。加巴喷丁类化合物（加巴喷丁和普瑞巴林）可用于治疗钙调神经磷酸酶介导的神经源性高血压。
BACKGROUNDCalcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by theCacna2d1gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor–induced synaptic NMDAR hyperactivity in the PVN and hypertension development.METHODSImmunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states.RESULTSProlonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin,Cacna2d1knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not inCacna2d1knockout mice.CONCLUSIONSα2δ-1 is essential for calcineurin inhibitor–induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor–induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor–induced neurogenic hypertension.