Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension.
Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension.
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DOI：
10.1111/jnc.12758
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发表时间：
2014-09
影响因子：
4.7
通讯作者：
Pan HL
中科院分区：
文献类型：
--
作者：
Pachuau J;Li DP;Chen SR;Lee HA;Pan HL
小电导钙激活K+（SK）通道调节神经元兴奋性。然而，对原发性高血压下丘脑室旁核（PVN）前交感神经元SK通道活动的变化知之甚少。SK通道、钙调蛋白和酪蛋白激酶II（CK 2）形成分子复合物。由于CK 2在自发性高血压大鼠（SHR）的PVN中上调，我们假设CK 2增加钙调蛋白磷酸化，并有助于降低SHR PVN前交感神经元中SK通道的活性。在Wistar-Kyoto（WKY）大鼠和SHR的脊髓投射PVN神经元上进行了逆行标记的穿孔全细胞记录。用apamin阻断SK通道显著增加WKY大鼠PVN神经元的放电频率，但在SHR中没有。CK 2抑制可恢复apamin对SHR PVN神经元放电活动的刺激作用。此外，在WKY大鼠的apamin敏感的SK电流和去极化诱导的PVN神经元的中后超极化电位显着大于SHR。CK 2抑制显著增加自发性高血压大鼠室旁核神经元SK通道电流和中后去极化电位。此外，CK 2介导的钙调素磷酸化水平在室旁核显着高于SHR比WKY大鼠。虽然在PVN中检测到SK 3，但其表达水平在SHR和WKY大鼠之间没有显著差异。我们的研究结果表明，CK 2介导的钙调蛋白磷酸化增加，并有助于减少SK通道功能的PVN前交感神经元在SHR。这一信息促进了我们对高血压时室旁核前交感神经元过度活跃和交感血管紧张度增加的机制的理解。
Small conductance calcium-activated K+ (SK) channels regulate neuronal excitability. However, little is known about changes in SK channel activity of presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) in essential hypertension. SK channels, calmodulin, and casein kinase II (CK2) form a molecular complex. Because CK2 is upregulated in the PVN in spontaneously hypertensive rats (SHRs), we hypothesized that CK2 increases calmodulin phosphorylation and contributes to diminished SK channel activity in PVN presympathetic neurons in SHRs. Perforated whole-cell recordings were performed on retrogradely labeled spinally projecting PVN neurons in Wistar-Kyoto (WKY) rats and SHRs. Blocking SK channels with apamin significantly increased the firing rate of PVN neurons in WKY rats but not in SHRs. CK2 inhibition restored the stimulatory effect of apamin on the firing activity of PVN neurons in SHRs. Furthermore, apamin-sensitive SK currents and depolarization-induced medium after-hyperpolarization potentials of PVN neurons were significantly larger in WKY rats than in SHRs. CK2 inhibition significantly increased the SK channel current and medium after-depolarization potential of PVN neurons in SHRs. In addition, CK2-mediated calmodulin phosphorylation level in the PVN was significantly higher in SHRs than in WKY rats. Although SK3 was detected in the PVN, its expression level did not differ significantly between SHRs and WKY rats. Our findings suggest that CK2-mediated calmodulin phosphorylation is increased and contributes to diminished SK channel function of PVN presympathetic neurons in SHRs. This information advances our understanding of the mechanisms underlying hyperactivity of PVN presympathetic neurons and increased sympathetic vasomotor tone in hypertension.
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