INTRACELLULAR SIGNALING IN ENDOCRINE CELLS

G蛋白偶联和酪氨酸激酶的作用机制 受体控制钙信号，而生理的 这种信号的含义在几个细胞中进行了研究 类型。观察到钙信号的三种模式：基线 振荡的，有尖峰的频率但没有尖峰的幅度 由激动剂浓度控制的；慢振荡的，具有 频率恒定、幅值可变的尖峰； 摇摆不定。钙信号的模式不是由 受体亚型，但受受体后事件影响。基线钙 由注射三磷酸肌醇引起的振荡 (InsP3)，以及接触离子霉素等化合物， 他西格宁和硫柳汞。然而，当细胞质 振荡器是由这些代理激活的，它只在 基础频率为5次/分，峰值频率不随时间变化 增加药物浓度，就像激动剂中常见的那样-和 InsP3刺激的细胞。相比之下，这两种类型的振荡 受管腔内钙的耗竭和 [Ca~(2+)]i的变化不受兰诺定的抑制。这个 电压敏感的钙通道也影响InsP3- 兴奋性促性腺激素细胞的依赖性钙振荡。在……里面 激动剂和Insp3刺激的细胞，持续的钙振荡 在3-15分钟后被超极化消除，尽管 细胞外培养上清液中钙的利用率。单人 去极化脉冲瞬间恢复了 二氢吡啶和细胞外钙持续增加- 敏感的态度。对去极化的反应显示出明显的 与膜电位相关的膜电位依赖性 稳态内向钙电流。此外，重复性的 短去极化脉冲调制频率的应用 激动剂和InsP3控制的尖峰作用。这些外在的驱动力 细胞外钙依赖的振荡对 钙泵阻滞剂thapsigargin，但不是ryanodine。一个 基于这些实验观测的数学模型给出了 对广泛的激动剂剂量的反应，包括 亚阈值响应、超阈值基线振荡 频率由[InsP3]确定的响应，双相 振荡和双相非振荡响应。该模型还 预测非受体介导的钙离子的存在 震荡。钙信号足以触发 初级反应基因(PRO)在几种类型白血病中的表达 内分泌细胞。在垂体促性腺激素细胞中，蛋白激酶C- 依赖于PRO的诱导被发现被调制为 生理变化对(Ca~(2+)]_i有正向和负向影响。 因此，钙信号的模式可能代表了一种有效的 内分泌等基因表达调控机制研究进展 单元类型。

The mechanisms by which G protein-coupled and tyrosine kinase receptors control calcium signaling, and the physiological implications of such signaling, were investigated in several cell types. Three patterns of calcium signaling were observed: base-line oscillatory, with the frequency but not the amplitude of spiking controlled by agonist concentration; slow-oscillatory, with a constant frequency and variable amplitude of spiking; and non- oscillatory. The pattern of calcium signaling was not determined by the receptor subtype but by post-receptor events. Base-line calcium oscillations were initiated by injection of inositol trisphosphate (InsP3), as well as by exposure to compounds such as ionomycin, thapsigargin, and thimerosal. However, when the cytoplasmic oscillator was activated by these agents, it operated only at the basal rate of 5/min and its spiking frequency did not change with increasing drug concentrations, as commonly occurs in agonist-and InsP3-stimulated cells. In contrast, both types of oscillations were affected by the depletion of intra-luminal calcium and by changes in [Ca2+]i, but were not inhibited by ryanodine. The voltage-sensitive calcium entry pathway also affected InsP3- dependent calcium oscillations in excitable gonadotrophs. In agonist- and Insp3-stimulated cells, sustained calcium oscillations were extinguished by hyperpolarization after 3-15 min despite the availability of calcium in the extracellular medium. Single depolarizing pulses transiently restored the amplitude of the sustained spiking in a dihydropyridine- and extracellular calcium- sensitive manner. The responses to depolarization showed a marked dependence on membrane potential that was correlated with the steady-state inward calcium current. In addition, the repetitive application of brief depolarizing pulses modulated the frequency of agonist and InsP3-controlled spiking. These extrinsically driven and extracellular calcium-dependent oscillations were sensitive to the calcium-pump blocker, thapsigargin, but not to ryanodine. A mathematical model based on these experimental observations gave responses to a wide range of agonist doses, including the subthreshold responses, superthreshold base-line oscillatory response with frequency determined by [InsP3], biphasic oscillatory, and biphasic non-oscillatory response. The model also predicted the existence of non-receptor-mediated calcium oscillations. Calcium signaling is sufficient to trigger the expression of primary response genes (PROS) in several types of endocrine cells. In pituitary gonadotrophs, the protein kinase C- dependent induction of PROs was found to be modulated both positively and negatively by physiological changes in (Ca2+]i. Thus, the pattern of calcium signaling may represent an efficient mechanism for the control of gene expression in endocrine and other cell types.