Large conductance Ca²⁺-activated K⁺ (BK) channels promote secretagogue-induced transition from spiking to bursting in murine anterior pituitary corticotrophs.
Large conductance Ca²⁺-activated K⁺ (BK) channels promote secretagogue-induced transition from spiking to bursting in murine anterior pituitary corticotrophs.
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DOI：
10.1113/jphysiol.2015.284471
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发表时间：
2015-03-01
期刊：
影响因子：
--
通讯作者：
Shipston MJ
中科院分区：
文献类型：
--
作者：
Duncan PJ;Şengül S;Tabak J;Ruth P;Bertram R;Shipston MJ
垂体前叶的促皮质细胞是电兴奋的，是下丘脑-垂体-肾上腺轴的组成部分，该轴控制对应激的神经内分泌反应。促肾上腺皮质激素细胞在基础条件下主要表现出单峰活动，在下丘脑促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP）刺激下转变为复杂的爆发行为;然而，控制爆发的潜在机制尚不清楚。在这项研究中，我们表明，CRH和AVP诱导不同模式的促肾上腺皮质激素细胞的电活动，我们使用的电生理方法结合数学建模显示这些差异的影响的离子机制。数据显示，促分泌素诱导的爆发依赖于大电导Ca 2+激活的K+（BK）通道，主要由CRH驱动，而AVP通过涉及非选择性阳离子电导激活的BK独立途径促进单峰频率增加。由于促肾上腺皮质激素细胞的兴奋性受CRH和AVP的不同调节，这可能使促肾上腺皮质激素细胞对不同的应激源做出适当的反应。垂体前叶促肾上腺皮质激素细胞是下丘脑-垂体-肾上腺（HPA）轴的核心组成部分，对应激的神经内分泌反应至关重要。促肾上腺皮质激素细胞是可兴奋的细胞，其接收来自两种下丘脑促分泌素（促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP））的输入以控制促肾上腺皮质激素（ACTH）的释放。虽然促肾上腺皮质激素细胞是自发活动的，并在响应CRH和AVP的电兴奋性和潜在的离子电导模式的兴奋性增加知之甚少。在这项研究中，我们使用电生理学，药理学和遗传学方法结合数学建模来研究CRH和AVP是否促进不同的电兴奋性模式，并询问大电导钙和电压激活钾（BK）通道在自发和促分泌素诱导的活动中的作用。我们发现，BK通道并没有发挥重要作用，在产生自发活动，但关键的过渡到突发响应CRH。相反，AVP促进单个尖峰频率的增加，这是一种独立于BK通道但依赖于背景非选择性电导的机制。CRH和AVP的共刺激导致复杂的兴奋性模式，包括单个尖峰频率和爆发的增加。促肾上腺皮质激素的兴奋性差异调节下丘脑促分泌素的能力提供了一种机制，差异控制促肾上腺皮质激素的兴奋性，在不同的应激反应。
Corticotroph cells of the anterior pituitary are electrically excitable and are an integral component of the hypothalamic‐pituitary‐adrenal axis which governs the neuroendocrine response to stress. Corticotrophs display predominantly single spike activity under basal conditions that transition to complex bursting behaviours upon stimulation by the hypothalamic secretagogues corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP); however, the underlying mechanisms controlling bursting are unknown. In this study, we show that CRH and AVP induce different patterns of corticotroph electrical activity, and we use an electrophysiological approach combined with mathematical modelling to show the ionic mechanisms for these differential effects. The data reveal that secretagogue‐induced bursting is dependent on large conductance Ca2+‐activated K+ (BK) channels and is driven primarily by CRH whereas AVP promotes an increase in single‐spike frequency through BK‐independent pathways involving activation of non‐selective cation conductances. As corticotroph excitability is differentially regulated by CRH and AVP this may allow corticotrophs to respond appropriately to different stressors. Anterior pituitary corticotroph cells are a central component of the hypothalamic‐pituitary‐adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophic hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modelling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium‐ and voltage‐activated potassium (BK) channels in spontaneous and secretagogue‐induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non‐selective conductances. Co‐stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors.
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