Mathematical Modeling of Neurons and Endocrine Cells

神经元和内分泌细胞的数学模型

• 批准号: 7733949
• 负责人: Arthur Sherman
• 金额: $ 6.6万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733949
• 关键词: Accounting; Action Potentials; Appearance; Area; Beta Cell; Calcium; Calcium Channel; Calcium-Activated Potassium Channel; Cations; Cells; Chemicals; Corticotropin; Coupled; Down-Regulation; Educational workshop; Elements; Endocrine; Endoplasmic Reticulum; Equation; Family; Feedback; Grouping; Hand; Hodgkin Disease; Hypothalamic structure; Insulin; Laboratories; Magnesium; Mediating; Mediator of activation protein; Membrane; Membrane Potentials; Modeling; National Institute of Child Health and Human Development; Nerve; Neurons; Nobel Prize; Ocular orbit; Organelles; Phase; Pituitary Gland; Potassium; Prolactin; Property; Role; Second Messenger Systems; Signaling Protein; Sodium; Somatostatin; Somatotropin; Somatotropin-Releasing Hormone; Specificity; Structure of beta Cell of islet; System; Transcriptional Activation; Up-Regulation; Work; base; cell type; interest; ion channel blocker; lactotroph; mathematical model; research study; salivary acinar cell; second messenger; tool

1. Pituitary somatotrophs secrete growth hormone spontaneously. This is controlled by burstinG oscillations in membrane potential (that is, action potentials occur in bursts separated by silent periods). This grouping together of action potentials produces an oscillatory but generally elevated calcium level, which is more efficient for secretion than isolated action potentials. Modulation up or down from this basic level is mediated by hypothalamic input of growth hormone releasing hormone (GHRH) and somatostatin (SRIF), respectively. We carried out mathematical modeling in parallel with experiments in the laboratory of S. Stojilkovic (NICHD) using channel blockers and ion substitution experiments to elucidate both the oscillation mechanism and its modulation. The key element of the model is negative feedback on large conductance (BK) calcium-activated potassium channels. We found that up-regulation could be explained by activation of an inward, non-selective cation current and/or deactivation of an inward rectifier potassium (KIR) channel. The reverse is true for down regulation. Finally, we found that the natural variability of oscillation period (a few seconds to tens of seconds) could be accounted for by different levels of BK conductance. The identity of the inward cation current is still unknown, but some of its properties have been clarified, such as that it is blocked by magnesium and carries sodium, which may help in ultimately identifying it. See Ref. # 1. 2. Like the pituitary somatotrophs described above, other pituitary cells (lactotrophs, which secrete prolactin; and corticotrophs, which secrete adrenocorticotropic hormone) show bursting oscillations that are similar in appearance. For example, the spikes on the plateau are small and noisy. We were interested to contrast models for such oscillations with models for more classically studied bursting in insulin-secreting pancreatic beta-cells. The latter look somewhat different, with much larger spikes and often, but not always, longer lasting plateaus. However, such quantitative differences are subtle and not reliable for distinguishing fundamental mechanisms. Instead, we found that models for the two types of oscillations can be distinguished by the stability of the depolarized (active) state. In the classic models for square-wave bursting in beta-cells, the spiking state consists of a family of stable periodic orbits. It is thus possible to reset cells in the silent phase of the burst to the active phase with brief depolarizations. This has been confirmed by experiments on beta-cells. The pituitary-type models, on the other hand, have small spikes corresponding to transients that decay slowly toward a weakly attracting upper steady state rather than stable oscillations. As a consequence, it is very difficult to reset the state from silent to active. This was a prominent topic of discussion at a recent workshop involving both theoreticians and experimentalists organized by the PI and colleagues, so there may be attempts to verify this prediction experimentally.

1。垂体生营养自发分泌生长激素。 这是通过膜电位爆炸（即，动作电位出现在静默周期隔开的爆发中）来控制的。 将这种动作电位组合在一起的分组产生振荡，但通常升高的钙水平，这比分离的动作电位更有效。 从该基本水平向上或向下的调节是由生长激素释放激素（GHRH）和生长抑素（SRIF）的下丘脑输入介导的。 我们使用通道阻滞剂和离子取代实验在S. stojilkovic（NICHD）实验中并行进行数学建模，以阐明振荡机制及其调节。 该模型的关键要素是对大电导（BK）钙激活的钾通道的负反馈。 我们发现，可以通过激活向内的非选择性阳离子电流和/或向内整流钾（KIR）通道停用上调来解释上调。 相反的情况对于下调是正确的。 最后，我们发现振荡周期的自然变异性（几秒钟到数十秒钟）可以通过不同水平的BK电导来解释。 内向阳离子电流的身份仍然未知，但是它的某些特性已被澄清，例如它被镁阻塞并携带钠，这可能有助于最终识别它。 参见参考。 ＃1。 2。就像上面描述的垂体种子营养不良一样，其他垂体细胞（分泌催乳素；和皮质营养的乳腺营养细胞，它们分泌肾上腺皮质性激素）显示出爆发的振荡，外观相似。 例如，高原上的尖峰小而嘈杂。 我们有兴趣将这种振荡的模型与模型进行对比模型，以用于胰岛素分泌胰岛β细胞时进行的更古典研究的爆发。 后者看起来有些不同，峰值较大，而且经常但并非总是持久的。 但是，这种定量差异是微妙的，对于区分基本机制并不可靠。 取而代之的是，我们发现两种类型的振荡模型可以​​通过去极化（活动）状态的稳定性来区分。 在Beta细胞中爆裂方波的经典模型中，尖峰状态由一个稳定的周期性轨道家庭组成。 因此，可以在短暂去极化的情况下将爆发的静默阶段重置为活动相。 在β细胞上的实验证实了这一点。 另一方面，垂体型模型的尖峰与瞬变相对应的小尖峰，这些瞬变速度缓慢地衰减弱吸引上部稳态而不是稳定的振荡。 结果，很难将状态从沉默重置为主动。 这是在最近的一个研讨会上进行讨论的重要主题，其中涉及PI及其同事组织的理论家和实验家，因此可能会尝试通过实验来验证这一预测。