Hypothalamic-pituitary-adrenal axis hyporesponsiveness to restraint stress in mice deficient for large-conductance calcium-and voltage-activated potassium (BK) channels
Hypothalamic-pituitary-adrenal axis hyporesponsiveness to restraint stress in mice deficient for large-conductance calcium-and voltage-activated potassium (BK) channels
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DOI：
10.1210/en.2007-0319
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发表时间：
2007-11-01
期刊：
影响因子：
4.8
通讯作者：
Shipston, Michael J.
中科院分区：
文献类型：
--
作者：
Brunton, Paula J.;Sausbier, Matthias;Shipston, Michael J.
压力会激活下丘脑-垂体-肾上腺 (HPA) 轴，从垂体前叶释放 ACTH，从肾上腺皮质释放糖皮质激素。压力还会激活交感神经系统，引起肾上腺髓质释放肾上腺素。大电导钙和电压激活钾 (BK) 通道与这些系统中细胞兴奋性的调节有关。在这里，我们使用 BK 通道成孔亚基遗传缺陷 (BK-/-) 的雌性小鼠，研究了 BK 通道在体内 HPA 轴调节中的功能作用。 HPA 中的 BK-/- 表型通过免疫组织化学、蛋白质印迹分析和促肾上腺皮质激素膜片钳记录得到证实。与野生型 (WT) 对照相比，BK-/- 小鼠中束缚应激诱导的 ACTH 和皮质酮血浆浓度显着减弱。这种应激反应低下与下丘脑室旁核（PVN）神经元的激活减少有关。与 WT 对照相比，BK-/- 小鼠 PVN 中 CRH 的基础表达显着降低，但精氨酸加压素 mRNA 的基础表达显着降低。与 WT 相比，BK-/- 小鼠的垂体前叶 ACTH 肽总含量显着降低，但阿黑皮质素原 mRNA 表达或促肾上腺皮质激素数量没有显着降低。然而，与 WT 小鼠相比，BK-/- 小鼠的垂体前叶促肾上腺皮质激素完全支持 ACTH 输出，在体外对促分泌素作出反应时释放出显着更大比例的储存 ACTH。这些结果支持 BK 通道在 HPA 轴的神经回路和内分泌输出中的重要作用，并表明 BK-/- 小鼠的应激反应低下主要是由于下丘脑 PVN 神经分泌神经元的激活减少所致。
Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing ACTH from the anterior pituitary gland and glucocorticoids from the adrenal cortex. Stress also activates the sympathetic nervous system, evoking adrenaline release from the adrenal medulla. Large-conductance calcium-and voltage-activated potassium (BK) channels have been implicated in regulation of cellular excitability in these systems. Here, we examine the functional role of BK channels in HPA axis regulation in vivo using female mice genetically deficient (BK-/-) for the pore-forming subunits of BK channels. BK-/- phenotype in the HPA was confirmed by immunohistochemistry, Western blot analysis, and corticotrope patch-clamp recording. Restraint stress-induced plasma concentrations of ACTH and corticosterone were significantly blunted in BK-/- mice compared with wild type (WT) controls. This stress hyporesponsiveness was associated with reduced activation of hypothalamic paraventricular nucleus (PVN) neurons. Basal expression of CRH, but not arginine vasopressin mRNA in the PVN was significantly lower in BK-/- mice compared with WT controls. Total anterior pituitary ACTH peptide content, but not proopiomelanocortin mRNA expression or corticotrope number, was significantly reduced in BK-/- mice compared with WT. However, anterior pituitary corticotropes from BK-/- mice fully supported ACTH output, releasing a significantly greater proportion of stored ACTH in response to secretagogue in vitro compared with WT. These results support an important role for BK channels in both the neural circuitry and endocrine output of the HPA axis and indicate that the stress hyporesponsiveness in BK-/- mice primarily results from reduced activation of hypothalamic PVN neurosecretory neurons.