Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons
Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons
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DOI：
10.1152/jn.01329.2006
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发表时间：
2007-05-01
影响因子：
2.5
通讯作者：
Pan, Hui-Lin
中科院分区：
文献类型：
--
作者：
Chen, Qian;Pan, Hui-Lin
下丘脑室旁核（PVN）是调节交感神经流出的重要部位。血管紧张素 II (Ang II) 可以激活 AT(1) 受体，通过抑制 GABA 能输入来刺激 PVN 前交感神经元。然而，人们对PVN中Ang II突触前作用所涉及的下游途径知之甚少。在这项研究中，利用大鼠脑切片中逆行标记的 PVN 神经元的全细胞记录，我们确定了 Ang II 对突触 GABA 释放到脊髓投射的 PVN 神经元的影响的信号传导机制。 Ang II 的浴应用可重复地降低荧光标记的 PVN 神经元中 GABA 能微型突触后抑制电流 (mIPSC) 的频率。 Ang II 未能改变用百日咳毒素处理的标记 PVN 神经元中 mIPSC 的频率。然而，在 CdCl2（一种电压门控 Ca2+ 通道阻滞剂）或 4-氨基吡啶（一种电压门控 K+ 通道阻滞剂）存在的情况下，Ang II 诱导的 mIPSC 抑制持续存在。有趣的是，用超氧化物歧化酶或 Mn(III) 四（4-苯甲酸）卟啉抑制超氧化物可完全阻止 Ang II 诱导的 mIPSC 减少。相比之下，用离子螯合剂去铁胺抑制羟基自由基的形成并没有显着改变Ang II的作用。这些发现表明，Ang II 对 PVN 突触 GABA 释放的突触前作用是由百日咳毒素敏感的 G(i/o) 蛋白介导的，而不是由电压门控 Ca2+ 和 K+ 通道介导的。 Ang II 通过活性氧，特别是超氧阴离子，减弱 PVN 前交感神经元的 GABA 能输入。
The hypothalamic para-ventricular nucleus (PVN) is an important site for the regulation of sympathetic outflow. Angiotensin II (Ang II) can activate AT(1) receptors to stimulate PVN presympathetic neurons through inhibition of GABAergic input. However, little is known about the downstream pathway involved in this presynaptic action of Ang II in the PVN. In this study, using whole cell recording from retrogradely labeled PVN neurons in rat brain slices, we determined the signaling mechanisms responsible for the effect of Ang II on synaptic GABA release to spinally projecting PVN neurons. Bath application of Ang II reproducibly decreased the frequency of GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in fluorescence-labeled PVN neurons. Ang II failed to change the frequency of mIPSCs in labeled PVN neurons treated with pertussis toxin. However, Ang II-induced inhibition of mIPSCs persisted in the presence of either CdCl2, a voltage-gated Ca2+ channel blocker, or 4-aminopyridine, a blocker of voltage-gated K+ channels. Interestingly, inhibition of superoxide with superoxide dismutase or Mn(III) tetrakis (4-benzoic acid) prophyrin completely blocked Ang II-induced decrease in mIPSCs. By contrast, inhibition of hydroxyl radical formation with the ion chelator deferoxamine did not significantly alter the effect of Ang II. These findings suggest that the presynaptic action of Ang II on synaptic GABA release in the PVN is mediated by the pertussis toxin-sensitive G(i/o) proteins but not by voltage-gated Ca2+ and K+ channels. Ang II attenuates GABAergic input to PVN presympathetic neurons through reactive oxygen species, especially superoxide anions.