Fletcher Patrick A, Zemkova Hana, Stojilkovic Stanko S, Sherman Arthur
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
Department of Cellular and Molecular Neuroendocrinology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; and.
J Neurophysiol. 2017 Jun 1;117(6):2298-2311. doi: 10.1152/jn.00948.2016. Epub 2017 Feb 22.
Pituitary corticotrophs fire action potentials spontaneously and in response to stimulation with corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), and such electrical activity is critical for calcium signaling and calcium-dependent adrenocorticotropic hormone secretion. These cells typically fire tall, sharp action potentials when spontaneously active, but a variety of other spontaneous patterns have also been reported, including various modes of bursting. There is variability in reports of the fraction of corticotrophs that are electrically active, as well as their patterns of activity, and the sources of this variation are not well understood. The ionic mechanisms responsible for CRH- and AVP-triggered electrical activity in corticotrophs are also poorly characterized. We use electrophysiological measurements and mathematical modeling to investigate possible sources of variability in patterns of spontaneous and agonist-induced corticotroph electrical activity. In the model, variation in as few as two parameters can give rise to many of the types of patterns observed in electrophysiological recordings of corticotrophs. We compare the known mechanisms for CRH, AVP, and glucocorticoid actions and find that different ionic mechanisms can contribute in different but complementary ways to generate the complex time courses of CRH and AVP responses. In summary, our modeling suggests that corticotrophs have several mechanisms at their disposal to achieve their primary function of pacemaking depolarization and increased electrical activity in response to CRH and AVP. We and others recently demonstrated that the electrical activity and calcium dynamics of corticotrophs are strikingly diverse, both spontaneously and in response to the agonists CRH and AVP. Here we demonstrate this diversity with electrophysiological measurements and use mathematical modeling to investigate its possible sources. We compare the known mechanisms of agonist-induced activity in the model, showing how the context of ionic conductances dictates the effects of agonists even when their target is fixed.
垂体促肾上腺皮质激素细胞会自发产生动作电位，并对促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP）的刺激作出反应，这种电活动对于钙信号传导和钙依赖性促肾上腺皮质激素分泌至关重要。这些细胞在自发活动时通常会产生高大、尖锐的动作电位，但也有其他各种自发模式的报道，包括多种爆发模式。关于有电活动的促肾上腺皮质激素细胞的比例及其活动模式的报道存在差异，且这种差异的来源尚不清楚。对CRH和AVP触发促肾上腺皮质激素细胞电活动的离子机制也知之甚少。我们使用电生理测量和数学建模来研究促肾上腺皮质激素细胞自发和激动剂诱导的电活动模式中可能存在差异的来源。在模型中，少至两个参数的变化就能产生促肾上腺皮质激素细胞电生理记录中观察到的许多类型的模式。我们比较了CRH、AVP和糖皮质激素作用的已知机制，发现不同的离子机制可以以不同但互补的方式起作用，以产生CRH和AVP反应的复杂时间进程。总之，我们的建模表明，促肾上腺皮质激素细胞有多种机制可用于实现其主要功能，即起搏去极化以及对CRH和AVP作出反应时增加电活动。我们和其他人最近证明，促肾上腺皮质激素细胞的电活动和钙动力学在自发状态下以及对激动剂CRH和AVP的反应中都非常多样。在这里，我们通过电生理测量证明了这种多样性，并使用数学建模来研究其可能的来源。我们在模型中比较了激动剂诱导活动的已知机制，展示了离子电导的背景如何决定激动剂的作用，即使其靶点是固定的。
