A-type K+ channels contribute to the prorenin increase of firing activity in hypothalamic vasopressin neurosecretory neurons.
A-type K+ channels contribute to the prorenin increase of firing activity in hypothalamic vasopressin neurosecretory neurons.
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A 型 K 通道有助于下丘脑加压素神经分泌神经元中肾素原的放电活动增加。
DOI：
10.1152/ajpheart.00216.2017
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Stern,JavierE
中科院分区：
文献类型：
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作者：
Pitra,Soledad;Stern,JavierE
最近的研究支持肾素原 (PR) 及其受体 (PRR) 对调节下丘脑、交感神经和心血管系统神经分泌流出物的重要贡献，包括在生理和心血管疾病条件下全身释放加压素 (VP)。尽管如此，精确的细胞机制和神经元/分子靶标的识别仍然未知。我们最近发现 PRR 在 VP 神经元中表达，并且它们的激活会增加神经元活动。然而，潜在的离子通道机制尚不清楚。在这里，我们对从增强型绿色荧光蛋白-VP 转基因大鼠获得的急性下丘脑切片中鉴定出的 VP 神经元进行膜片钳电生理学分析。电压钳记录显示，PR 抑制 A 型 K+ 电流的幅度（IA；-25 mV 时约 50%），这是一种抑制 VP 放电活动的阈下电压依赖性电流。 PR 还增加了 IA 的失活率，并将稳态电压依赖性失活功能转向更超极化的膜电位（约 7 mV 偏移），从而导致在任何给定膜电位下激活的通道可用性减少。 PR 还抑制 IA（“窗口”电流）的持续分量。当 IA 被 4-氨基吡啶阻断时，PR 介导的动作电位波形变化和放电活动增加被阻断。最后，PR 未能增加视上核/室旁核内的超氧化物产生，并且在用 SOD 模拟 tempol 处理的切片中，PR 兴奋作用持续存在。总而言之，这些实验表明 PR 对加压素神经元的兴奋作用涉及对 IA 的抑制，部分原因是其电压依赖性失活特性的增加。此外，我们的结果表明，PR 效应并不涉及氧化应激的增加。新的和值得注意的在这里，我们证明肾素原/肾素原受体是调节加压素放电活性的重要信号单元，从而调节全身激素释放。我们确定 A 型 K+ 通道是介导肾素原刺激加压素神经元活动的关键分子靶点，因此是心血管疾病中神经体液激活的潜在治疗靶点。
Recent studies have supported an important contribution of prorenin (PR) and its receptor (PRR) to the regulation of hypothalamic, sympathetic, and neurosecretory outflows to the cardiovascular system, including systemic release of vasopressin (VP), both under physiological and cardiovascular disease conditions. Still, the identification of precise cellular mechanisms and neuronal/molecular targets remain unknown. We have recently shown that PRR is expressed in VP neurons and that their activation increases neuronal activity. However, the underlying ionic channel mechanisms are undefined. Here, we performed patch-clamp electrophysiology from identified VP neurons in acute hypothalamic slices obtained from enhanced green fluorescent protein-VP transgenic rats. Voltage-clamp recordings showed that PR inhibited the magnitude of A-type K+current (IA; ~50% at −25 mV), a subthreshold voltage-dependent current that restrains VP firing activity. PR also increased the inactivation rate ofIAand shifted the steady-state voltage-dependent inactivation function toward more hyperpolarized membrane potential (~7 mV shift), thus resulting in less channel availability to be activated at any given membrane potential. PR also inhibited a sustained component ofIA(“window” current). PR-mediated changes in action potential waveform and increased firing activity were occluded whenIAwas blocked by 4-aminopyridine. Finally, PR failed to increase superoxide production within the supraoptic nucleus/paraventricular nucleus, and PR excitatory effects persisted in slices treated with the SOD mimetic tempol. Taken together, these experiments indicated that PR excitatory effects on vasopressin neurons involve inhibition ofIA, due, in part, to increases in its voltage-dependent inactivation properties. Moreover, our results indicate that PR effects did not involve an increase in oxidative stress.NEW & NOTEWORTHYHere, we demonstrate that prorenin/the prorenin receptor is an important signaling unit for the regulation of vasopressin firing activity and, thus, systemic hormonal release. We identified A-type K+channels as key molecular targets mediating prorenin stimulation of vasopressin neuronal activity, thus standing as a potential therapeutic target for neurohumoral activation in cardiovascular disease.