Mechanisms of cyclic AMP compartmentation revealed by computational models.
Mechanisms of cyclic AMP compartmentation revealed by computational models.
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DOI：
10.1085/jgp.201311044
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Polanowska-Grabowska R
中科院分区：
文献类型：
--
作者：
Saucerman JJ;Greenwald EC;Polanowska-Grabowska R
与Jeffrey J. Saucerman的通信：jsaucerman@ virginia。本文中使用的缩写：AC，腺苷酸环化酶; AKAP，A激酶锚定蛋白; MRP，多药耐药蛋白; PDE，磷酸二酯酶; PGE 1，前列腺素E1。由计算模型提供。计算模型已用于评估一系列潜在的cAMP区室化机制：局部cAMP合成、局部cAMP降解、扩散的物理屏障、cAMP缓冲、细胞形状和cAMP输出（见图1）。在简要总结了关键的激励实验测量后，我们将描述与这些潜在机制相关的模型预测。然后，我们将讨论未来的方向，包括必要的实验验证的关键模型的预测和纳入cAMP compartmentation到多尺度计算models.Experimental测量cAMP compartmentation生化方法。通过细胞分级分离和放射免疫测定法进行cAMP区室化的初始测量。Corbin等人（1977）分离了兔心脏匀浆的颗粒和可溶性部分，发现颗粒部分中约一半的总cAMP含量与PKA调节亚基结合。增加cAMP合成或阻断其降解导致可溶性级分中的[cAMP]不成比例地增加（Corbin等人，1977年）。尽管β-肾上腺素能受体和前列腺素受体两者的活化增加了心脏匀浆中的可溶性cAMP和PKA活性，但只有β-肾上腺素能受体增加了颗粒级分中的cAMP和PKA（Hayes等人，1980）并引发收缩性和糖原代谢的下游增加（Brunton等人，1979年）。这些生物化学方法的局限性在于它们破坏了完整的细胞环境，并且颗粒部分含有广泛的膜、肌节和细胞器。
Correspondence to Jeffrey J. Saucerman: jsaucerman@ virginia. edu Abbreviations used in this paper: AC, adenylyl cyclase; AKAP, A kinase–anchoring protein; MRP, multidrug resistance protein; PDE, phosphodiesterase; PGE1, prostaglandin E1. provided by computational models. Computational models have been used to evaluate a range of potential cAMP compartmentation mechanisms: localized cAMP synthesis, localized cAMP degradation, physical barriers to diffusion, cAMP buffering, cell shape, and cAMP export (see Fig. 1). After briefly summarizing key motivating experimental measurements, we will describe model predictions related to each of these potential mechanisms. We will then discuss future directions including necessary experimental validations of key model predictions and the incorporation of cAMP compartmentation into multi-scale computational models.Experimental measurements of cAMP compartmentation Biochemical approaches. The initial measurements of cAMP compartmentation were performed by cellular fractionation and radioimmunoassay. Corbin et al.(1977) isolated particulate and soluble fractions of rabbit heart homogenates, finding that about half of the total cAMP content was bound to PKA regulatory subunit in the particulate fraction. Increasing cAMP synthesis or blocking its degradation caused disproportionate [cAMP] increases in the soluble fraction (Corbin et al., 1977). Although activation of both ß-adrenergic and prostaglandin receptors increased soluble cAMP and PKA activity in heart homogenates, only ß-adrenergic receptors elevated cAMP and PKA in the particulate fraction (Hayes et al., 1980) and triggered downstream increases in contractility and glycogen metabolism (Brunton et al., 1979). A limitation to these biochemical approaches is that they destroy the intact cellular environment, and particulate fractions contain a wide range of membranes, sarcomeres, and organelles.
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