Bush2016 - Simplified Carrousel model of GPCR

Bush2016 - Simplified Carrousel model of
GPCR

This model is described in the article:

Yeast GPCR signaling
reflects the fraction of occupied receptors, not the
number.

Bush A, Vasen G, Constantinou A,
Dunayevich P, Patop IL, Blaustein M, Colman-Lerner A.
Mol. Syst. Biol. 2016 Dec; 12(12):
898
Abstract:

According to receptor theory, the effect of a ligand depends
on the amount of agonist-receptor complex. Therefore, changes
in receptor abundance should have quantitative effects.
However, the response to pheromone in Saccharomyces cerevisiae
is robust (unaltered) to increases or reductions in the
abundance of the G-protein-coupled receptor (GPCR), Ste2,
responding instead to the fraction of occupied receptor. We
found experimentally that this robustness originates during
G-protein activation. We developed a complete mathematical
model of this step, which suggested the ability to compute
fractional occupancy depends on the physical interaction
between the inhibitory regulator of G-protein signaling (RGS),
Sst2, and the receptor. Accordingly, replacing Sst2 by the
heterologous hsRGS4, incapable of interacting with the
receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2
interaction restored robustness. Taken together with other
results of our work, we conclude that this GPCR pathway
computes fractional occupancy because ligand-bound GPCR-RGS
complexes stimulate signaling while unoccupied complexes
actively inhibit it. In eukaryotes, many RGSs bind to specific
GPCRs, suggesting these complexes with opposing activities also
detect fraction occupancy by a ratiometric measurement. Such
complexes operate as push-pull devices, which we have recently
described.

This model is hosted on
BioModels Database
and identified by:
BIOMD0000000637.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.

To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.

Bush2016——G蛋白偶联受体（G Protein-Coupled Receptor, GPCR）简化转盘模型

本模型对应的发表文章为：《酵母G蛋白偶联受体信号通路反映受体占据分数而非受体数量》，作者包括Bush A、Vasen G、Constantinou A、Dunayevich P、Patop IL、Blaustein M、Colman-Lerner A，发表于《分子系统生物学》（Mol. Syst. Biol.）2016年12月；12(12):898。

摘要：
根据受体理论，配体的效应取决于激动剂-受体复合物的总量，因此受体丰度的变化应产生定量调控效应。然而，酿酒酵母（Saccharomyces cerevisiae）对信息素的响应对G蛋白偶联受体Ste2的丰度增减具有鲁棒性（不受影响），其响应反而取决于受体的占据分数。我们通过实验证实，该鲁棒性起源于G蛋白激活阶段。我们构建了该信号步骤的完整数学模型，结果显示，计算受体占据分数的能力依赖于G蛋白信号转导调节因子（Regulator of G-protein Signaling, RGS）Sst2与受体之间的物理相互作用。据此，将Sst2替换为无法与受体结合的异源人类RGS4（hsRGS4）后，该鲁棒性消失；反之，强制hsRGS4与Ste2结合则可恢复鲁棒性。结合本团队其他研究结果，我们得出结论：该GPCR通路能够计算受体占据分数，因为结合配体的GPCR-RGS复合物可激活信号转导，而未结合配体的复合物则会主动抑制信号转导。在真核生物中，诸多RGS蛋白可与特定GPCR结合，这提示这类具有双向活性的复合物同样可通过比例测量的方式检测受体占据分数。此类复合物可作为推拉装置发挥作用，我们已在近期对此进行了阐述。

本模型已托管于生物模型数据库（BioModels Database），其唯一标识为BIOMD0000000637。引用生物模型数据库的规范表述为：生物模型数据库：面向已发表定量动力学模型的增强型、经整理与注释的资源。

在法律允许的最大范围内，本编码模型的所有著作权及相关或邻接权利已被奉献至全球公共领域。如需了解更多详细信息，请参阅CC0公共领域贡献声明。