CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension
CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension
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DOI：
10.1523/jneurosci.2141-17.2017
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发表时间：
2017-11-01
影响因子：
5.3
通讯作者：
Pan, Hui-Lin
中科院分区：
文献类型：
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作者：
Li, De-Pei;Zhou, Jing-Jing;Pan, Hui-Lin
下丘脑室旁核（PVN）的NMDAR活性增加，并与高血压患者交感血管舒张性增强密切相关。钙/钙调素依赖性蛋白激酶II （CaMKII）结合并调节NMDAR活性。在本研究中，我们确定了CaMKII在调节雄性自发性高血压大鼠PVN前交感神经元NMDAR活性中的作用。在SHRs和雄性Wistar-Kyoto （WKY）大鼠脊髓突起PVN神经元中记录了nmda介导的EPSCs和膨化nmda引发的电流。逆行标记PVN神经元诱发NMDA - epscs的基底振幅和膨化NMDA电流在SHRs中显著高于WKY大鼠。CaMKII抑制剂autocam肽-2相关抑制肽（AIP）使SHRs标记PVN神经元中NMDA - epscs和膨化NMDA电流的增加幅度正常化，但对WKY大鼠没有影响。AIP治疗也使SHRs PVN神经元中nmdar介导的微型EPSCs的高频率正常化。camkii介导的GluN2B丝氨酸1303 （S1303）在PVN中的磷酸化水平在SHRs中显著高于WKY大鼠，而在海马和额叶皮质中没有磷酸化水平。SHRs患者行腹腔神经节切除术后血压降低并没有改变PVN中磷酸化GluN2B S1303水平的升高。此外，向PVN显微注射AIP可显著降低SHRs的动脉血压和腰交感神经放电。我们的研究结果表明，CaMKII活性在PVN中增加，并有助于增强突触前和突触后NMDAR活性，从而提高高血压患者的交感血管舒缩张力。
NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats. The basal amplitude of evoked NMDAR-EPSCs and puff NMDA currents in retrogradely labeled PVN neurons were significantly higher in SHRs than in WKY rats. The CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP) normalized the increased amplitude of NMDAR-EPSCs and puff NMDA currents in labeled PVN neurons in SHRs but had no effect in WKY rats. Treatment with AIP also normalized the higher frequency of NMDAR-mediated miniature EPSCs of PVN neurons in SHRs. CaMKII-mediated phosphorylation level of GluN2B serine 1303 (S1303) in the PVN, but not in the hippocampus and frontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased level of phosphorylated GluN2B S1303 in the PVN. In addition, microinjection of AIP into the PVN significantly reduced arterial blood pressure and lumbar sympathetic nerve discharges in SHRs. Our findings suggest that CaMKII activity is increased in the PVN and contributes to potentiated presynaptic and postsynaptic NMDAR activity to elevate sympathetic vasomotor tone in hypertension.