Control of hypothalamic-pituitary-adrenal stress axis activity by the intermediate conductance calcium-activated potassium channel, SK4
Control of hypothalamic-pituitary-adrenal stress axis activity by the intermediate conductance calcium-activated potassium channel, SK4
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DOI：
10.1113/jphysiol.2011.219378
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发表时间：
2011-12-01
影响因子：
5.5
通讯作者：
Shipston, Michael J.
中科院分区：
文献类型：
--
作者：
Liang, Zhi;Chen, Lie;Shipston, Michael J.
垂体前叶促肾上腺皮质激素细胞是调节下丘脑-垂体-肾上腺（HPA）轴和应激神经内分泌反应的主要控制点。虽然已知促肾上腺皮质激素细胞是可电兴奋的，但控制促肾上腺皮质激素细胞电特性的离子通道知之甚少。在这里，我们利用慢病毒转导系统，使明确的识别活的小鼠促肾上腺皮质激素细胞的文化。我们表明，促肾上腺皮质激素细胞显示高度异质性的自发动作电位放电模式和他们的静息膜电位调制的背景钠电导。生理浓度的促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP）引起促肾上腺皮质激素细胞的去极化，导致动作电位放电持续增加。外向钾传导的一个主要组成部分介导的中间电导钙激活（SK 4）钾通道。用TRAM-34抑制SK 4通道导致促肾上腺皮质激素细胞兴奋性增加，并在体外夸大CRH/AVP刺激的ACTH分泌。根据体内SK 4通道的生理作用，在缺乏SK 4通道的基因靶向小鼠（Kcnn 4（-/-））中，束缚应激诱导的血浆ACTH和皮质酮浓度显著增强。此外，Kcnn 4（-/-）突变小鼠在束缚后显示出增强的下丘脑c-fos和nur 77 mRNA表达，表明增加的神经元活化。因此，在Kcnn 4（-/-）小鼠中观察到的应激高反应性是由促分泌素诱导的垂体前叶促肾上腺皮质激素分泌增强引起的，也可能涉及下丘脑驱动增加，从而表明SK 4通道在HPA轴功能中的重要作用。
The anterior pituitary corticotroph is a major control point for the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. Although corticotrophs are known to be electrically excitable, ion channels controlling the electrical properties of corticotrophs are poorly understood. Here, we exploited a lentiviral transduction system to allow the unequivocal identification of live murine corticotrophs in culture. We demonstrate that corticotrophs display highly heterogeneous spontaneous action-potential firing patterns and their resting membrane potential is modulated by a background sodium conductance. Physiological concentrations of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) cause a depolarization of corticotrophs, leading to a sustained increase in action potential firing. A major component of the outward potassium conductance was mediated via intermediate conductance calcium-activated (SK4) potassium channels. Inhibition of SK4 channels with TRAM-34 resulted in an increase in corticotroph excitability and exaggerated CRH/AVP-stimulated ACTH secretion in vitro. In accordance with a physiological role for SK4 channels in vivo, restraint stress-induced plasma ACTH and corticosterone concentrations were significantly enhanced in gene-targeted mice lacking SK4 channels (Kcnn4(-/-)). In addition, Kcnn4(-/-) mutant mice displayed enhanced hypothalamic c-fos and nur77 mRNA expression following restraint, suggesting increased neuronal activation. Thus, stress hyperresponsiveness observed in Kcnn4(-/-) mice results from enhanced secretagogue-induced ACTH output from anterior pituitary corticotrophs and may also involve increased hypothalamic drive, thereby suggesting an important role for SK4 channels in HPA axis function.