Chronic stress facilitates bursting electrical activity in pituitary corticotrophs
Chronic stress facilitates bursting electrical activity in pituitary corticotrophs
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DOI：
10.1113/jp282367
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发表时间：
2021-12-23
影响因子：
5.5
通讯作者：
Shipston, Michael J.
中科院分区：
文献类型：
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作者：
Duncan, Peter J.;Fazli, Mehran;Shipston, Michael J.
适当的应激反应的协调依赖于垂体前叶促肾上腺皮质激素的兴奋性，下丘脑促分泌素和糖皮质激素的负反馈。促肾上腺皮质激素细胞兴奋性的一个关键决定因素是大电导钙和电压激活（BK）钾通道，其对于促进促肾上腺皮质激素释放激素（CRH）诱导的爆发（增强促肾上腺皮质激素分泌）至关重要。以往的研究表明，慢性应激（CS）后下丘脑-垂体-肾上腺轴过度兴奋部分是促肾上腺皮质激素分泌增加的功能。因此，我们假设慢性应激通过BK依赖性机制促进促肾上腺皮质激素细胞的兴奋性。CS小鼠的促肾上腺皮质激素细胞显示自发爆发的显著增加，这被BK阻断剂paxilline抑制。数学模型表明，BK通道激活的时间常数，加上BK通道的功能耦合到L-型Ca 2+通道的属性和比例决定了爆发活动。令人惊讶的是，CS促肾上腺皮质激素细胞（但不是无压力的）显示CRH诱导的爆裂，即使大多数BK通道被抑制paxilline，这一建模表明是一个后果的随机行为的一小部分BK通道耦合到L-型Ca 2+通道。我们的数据表明，在一个小数目的BK通道的随机行为的变化可以微调促肾上腺皮质激素细胞的兴奋性，通过应力诱导的BK通道特性的变化。重要的是，BK通道功能的调节是高度依赖于上下文的，允许在大范围的时间域和健康和疾病中的生理挑战上动态控制促肾上腺皮质激素细胞的兴奋性。这可能发生在其他BK表达内分泌细胞中，对它们调节的生理过程和治疗潜力具有重要意义。关键点慢性应激（CS）预计修改垂体前叶促肾上腺皮质激素细胞的电兴奋性。从CS雄性小鼠分离的促肾上腺皮质激素细胞的电生理记录显示自发的电爆发行为相比，紧张性尖峰行为的非应激促肾上腺皮质激素细胞。CS促肾上腺皮质激素细胞增加的自发爆发是BK依赖性的，数学建模表明，BK通道的激活时间常数、特性和比例在功能上与L型钙通道偶联，决定了爆发活性的促进。CS（但不是无应激）促肾上腺皮质激素细胞显示促肾上腺皮质激素释放激素诱导的爆发，即使大多数BK通道被抑制，这可以解释为随机行为的少数BK通道具有不同的属性。促肾上腺皮质激素细胞的兴奋性可以通过少量BK通道的随机行为进行微调，这取决于它们的特性和与L型钙通道的功能共定位，以控制不同时间域和生理挑战中的促肾上腺皮质激素细胞的兴奋性。
Coordination of an appropriate stress response is dependent upon anterior pituitary corticotroph excitability in response to hypothalamic secretagogues and glucocorticoid negative feedback. A key determinant of corticotroph excitability is large conductance calcium- and voltage-activated (BK) potassium channels that are critical for promoting corticotrophin-releasing hormone (CRH)-induced bursting that enhances adrenocorticotrophic hormone secretion. Previous studies revealed hypothalamic-pituitary-adrenal axis hyperexcitability following chronic stress (CS) is partly a function of increased corticotroph output. Thus, we hypothesise that chronic stress promotes corticotroph excitability through a BK-dependent mechanism. Corticotrophs from CS mice displayed significant increase in spontaneous bursting, which was suppressed by the BK blocker paxilline. Mathematical modelling reveals that the time constant of BK channel activation, plus properties and proportion of BK channels functionally coupled to L-type Ca2+ channels determines bursting activity. Surprisingly, CS corticotrophs (but not unstressed) display CRH-induced bursting even when the majority of BK channels are inhibited by paxilline, which modelling suggests is a consequence of the stochastic behaviour of a small number of BK channels coupled to L-type Ca2+ channels. Our data reveal that changes in the stochastic behaviour of a small number of BK channels can finely tune corticotroph excitability through stress-induced changes in BK channel properties. Importantly, regulation of BK channel function is highly context dependent allowing dynamic control of corticotroph excitability over a large range of time domains and physiological challenges in health and disease. This is likely to occur in other BK-expressing endocrine cells, with important implications for the physiological processes they regulate and the potential for therapy. Key points Chronic stress (CS) is predicted to modify the electrical excitability of anterior pituitary corticotrophs. Electrophysiological recordings from isolated corticotrophs from CS male mice display spontaneous electrical bursting behaviour compared to the tonic spiking behaviour of unstressed corticotrophs. The increased spontaneous bursting from CS corticotrophs is BK-dependent and mathematical modelling reveals that the time constant of activation, properties and proportion of BK channels functionally coupled to L-type calcium channels determines the promotion of bursting activity. CS (but not unstressed) corticotrophs display corticotrophin-releasing hormone-induced bursting even when the majority of BK channels are pharmacologically inhibited, which can be explained by the stochastic behaviour of a small number of BK channels with distinct properties. Corticotroph excitability can be finely tuned by the stochastic behaviour of a small number of BK channels dependent on their properties and functional co-localisation with L-type calcium channels to control corticotroph excitability over diverse time domains and physiological challenges.