Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension.
Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension.
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DOI：
10.1523/jneurosci.1147-11.2011
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发表时间：
2011-06-01
期刊：
影响因子：
--
通讯作者：
Pan HL
中科院分区：
文献类型：
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作者：
Ye ZY;Li DP;Li L;Pan HL
室旁核（PVN）的交感神经能输入增加是高血压高交感神经流出的重要原因，但相关的分子机制尚不清楚。在这里，我们确定了蛋白激酶CK 2的作用增加N-甲基-D-天冬氨酸受体（NMDAR）的活动在脊髓投射PVN神经元和交感神经血管紧张素在自发性高血压大鼠（SHR）。选择性CK 2抑制剂5，6-二氯-1-β-D-呋喃核糖基苯并咪唑（DRB）或4，5，6，7-四溴苯并三唑（TBB）可显著降低SHR室旁核标记神经元的兴奋性突触后电流（EPSC）频率，但对正常血压大鼠无明显影响。此外，DRB取消了NMDAR拮抗剂AP 5对SHR mEPSC频率的抑制作用。DRB或TBB处理显著降低SHR诱发的NMDA-EPSC的振幅，但不降低AMPA-EPSC的振幅。此外，DRB显着降低自发性高血压大鼠的PVN神经元的放电活动，而不是在WKY大鼠。SHR室旁核CK 2 α膜蛋白水平显著高于WKY大鼠，而脑干和前额叶皮质CK 2 α膜蛋白水平无显著差异。SHR腹腔神经节切除术后血压降低，CK 2 α水平升高，DRB对mEPSCs和NMDA-EPSCs的作用无明显改变。此外，侧脑室内注射DRB不仅能显着降低血压和腰交感神经放电，而且还能消除PVN微量注射AP 5对SHR交感神经活动的抑制作用。我们的研究结果表明，增加CK 2活性的关键是有助于增加突触前和突触后NMDAR活性的PVN和交感神经血管紧张素升高原发性高血压。
Increased glutamatergic input in the paraventricular nucleus (PVN) is important for high sympathetic outflow in hypertension, but the associated molecular mechanisms remain unclear. Here we determined the role of protein kinase CK2 in increased N-methyl-D-aspartate receptor (NMDAR) activity in spinally projecting PVN neurons and sympathetic vasomotor tone in spontaneously hypertensive rats (SHR). The selective CK2 inhibitors 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) significantly decreased the frequency of miniature excitatory postsynaptic currents (EPSCs) of labeled PVN neurons in SHR but not in Wistar-Kyoto (WKY) normotensive rats. Also, DRB abolished the inhibitory effect of the NMDAR antagonist AP5 on the frequency of mEPSCs in SHR. Treatment with DRB or TBB significantly reduced the amplitude of evoked NMDA-EPSCs but not AMPA-EPSCs in SHR. Furthermore, DRB significantly decreased the firing activity of PVN neurons in SHR but not in WKY rats. The membrane protein level of CK2α in the PVN, but not brainstem and prefrontal cortex, was significantly higher in SHR than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHR did not alter the increased CK2α level and the effects of DRB on mEPSCs and NMDA-EPSCs. In addition, intracerebroventricular injection of DRB not only significantly reduced blood pressure and lumbar sympathetic nerve discharges but also eliminated the inhibitory effect of AP5 microinjected into the PVN on sympathetic nerve activity in SHR. Our findings suggest that augmented CK2 activity critically contributes to increased pre- and postsynaptic NMDAR activity in the PVN and elevated sympathetic vasomotor tone in essential hypertension.