Models of IP3 and Ca2+ oscillations:: Frequency encoding and identification of underlying feedbacks
Models of IP3 and Ca2+ oscillations:: Frequency encoding and identification of underlying feedbacks
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DOI：
10.1529/biophysj.105.072249
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发表时间：
2006-05-01
影响因子：
3.4
通讯作者：
Höfer, T
中科院分区：
文献类型：
--
作者：
Politi, A;Gaspers, LD;Höfer, T
通过钙释放信使1，4，5-三磷酸肌醇（IP 3）起作用的激素引起细胞内钙振荡，这归因于IP 3受体上的钙反馈。最近的研究表明，IP 3水平与细胞质钙浓度一起振荡。为了研究这种现象的功能意义，我们已经开发了两个第二信使相互作用的数学模型。该模型解释了钙对IP 3代谢的正反馈和负反馈，分别由磷脂酶C和IP 3 3-激酶的钙激活介导。耦合的IP 3和钙振荡有一个大大扩展的频率范围相比，与钳位IP 3获得的钙波动。因此，反馈在支持在许多细胞类型中观察到的激素浓度的有效频率编码方面可以是生理上重要的。反馈的这种作用取决于IP 3的周转率。为了形成振荡，正反馈需要快速的IP 3周转，而负反馈需要缓慢的IP 3周转。IP 3结合蛋白的异位表达已被用于降低IP 3周转率实验，导致剂量依赖性减缓和最终淬灭的Ca 2+振荡。这些结果与基于Ca 2+对IP 3产生的正反馈的模型一致。
Hormones that act through the calcium-releasing messenger, inositol 1,4,5-trisphosphate (IP3), cause intracellular calcium oscillations, which have been ascribed to calcium feedbacks on the IP3 receptor. Recent studies have shown that IP3 levels oscillate together with the cytoplasmic calcium concentration. To investigate the functional significance of this phenomenon, we have developed mathematical models of the interaction of both second messengers. The models account for both positive and negative feedbacks of calcium on IP3 metabolism, mediated by calcium activation of phospholipase C and IP3 3-kinase, respectively. The coupled IP3 and calcium oscillations have a greatly expanded frequency range compared to calcium fluctuations obtained with clamped IP3. Therefore the feedbacks can be physiologically important in supporting the efficient frequency encoding of hormone concentration observed in many cell types. This action of the feedbacks depends on the turnover rate of IP3. To shape the oscillations, positive feedback requires fast IP3 turnover, whereas negative feedback requires slow IP3 turnover. The ectopic expression of an IP3 binding protein has been used to decrease the rate of IP3 turnover experimentally, resulting in a dose-dependent slowing and eventual quenching of the Ca2+ oscillations. These results are consistent with a model based on positive feedback of Ca2+ on IP3 production.