Quantitative in silico Analysis of Neurotransmitter Pathways Under Steady State Conditions.
Quantitative in silico Analysis of Neurotransmitter Pathways Under Steady State Conditions.
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DOI：
10.3389/fendo.2013.00137
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发表时间：
2013
影响因子：
5.2
通讯作者：
Somersalo E
中科院分区：
文献类型：
--
作者：
Calvetti D;Somersalo E
涉及星形胶质细胞、谷氨酸能和GABA能神经元的脑组织中谷氨酸/GABA-谷氨酰胺循环的建模导致包括神经递质合成、穿梭和降解的复杂区室化代谢网络。如果没有先进的计算工具，就很难定量跟踪可能的情景并确定可行的情景。在这篇文章中，我们遵循一个基于采样的计算范式来分析在一个多室系统建模星形胶质细胞，氨能，GABA能神经元的生化网络，并解决一些问题的细节发射机循环，特别强调氨穿梭星形胶质细胞和神经元之间，和发射机GABA的合成。更具体地说，我们认为丙氨酸-乳酸穿梭，支链氨基酸穿梭，和谷氨酰胺-谷氨酸循环的联合行动，以及谷氨酸脱氢酶（GDH）活性的作用。当对反应和转运通量施加最小量的结合约束时，优选的化学计量稳态平衡需要神经元中不切实际的高还原GDH活性，这表明需要包括在随后的计算机模拟中的额外的结合常数。统计通量平衡分析还表明亮氨酸转运作为谷氨酰胺的替代物在化学计量上可行的作用，用于补充神经元中的谷氨酸池。
The modeling of glutamate/GABA-glutamine cycling in the brain tissue involving astrocytes, glutamatergic and GABAergic neurons leads to a complex compartmentalized metabolic network that comprises neurotransmitter synthesis, shuttling, and degradation. Without advanced computational tools, it is difficult to quantitatively track possible scenarios and identify viable ones. In this article, we follow a sampling-based computational paradigm to analyze the biochemical network in a multi-compartment system modeling astrocytes, glutamatergic, and GABAergic neurons, and address some questions about the details of transmitter cycling, with particular emphasis on the ammonia shuttling between astrocytes and neurons, and the synthesis of transmitter GABA. More specifically, we consider the joint action of the alanine-lactate shuttle, the branched chain amino acid shuttle, and the glutamine-glutamate cycle, as well as the role of glutamate dehydrogenase (GDH) activity. When imposing a minimal amount of bound constraints on reaction and transport fluxes, a preferred stoichiometric steady state equilibrium requires an unrealistically high reductive GDH activity in neurons, indicating the need for additional bound constants which were included in subsequent computer simulations. The statistical flux balance analysis also suggests a stoichiometrically viable role for leucine transport as an alternative to glutamine for replenishing the glutamate pool in neurons.