Computational modeling reveals how interplay between components of a GTPase-cycle module regulates signal transduction

被引:35
作者
Bornheimer, SJ
Maurya, MR
Farquhar, MG
Subramaniam, S
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, San Diego Supercomp Ctr, La Jolla, CA 92093 USA
关键词
D O I
10.1073/pnas.0407009101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Heterotrimeric G protein signaling is regulated by signaling modules composed of heterotrimeric G proteins, active G protein-coupled receptors (Rs), which activate G proteins, and GTPase-activating proteins (GAPs), which deactivate G proteins. We term these modules GTPase-cycle modules. The local concentrations of these proteins are spatially regulated between plasma membrane microdomains and between the plasma membrane and cytosol, but no data or models are available that quantitatively explain the effect of such regulation on signaling. We present a computational model of the GTPase-cycle module that predicts that the interplay of local G protein, R, and GAP concentrations gives rise to 16 distinct signaling regimes and numerous intermediate signaling phenomena. The regimes suggest alternative modes of the GTPase-cycle module that occur based on defined local concentrations of the component proteins. In one mode, signaling occurs while G protein and receptor are unclustered and GAP eliminates signaling; in another, G protein and receptor are clustered and GAP can rapidly modulate signaling but does not eliminate it. Experimental data from multiple GTPase-cycle modules is interpreted in light of these predictions. The latter mode explains previously paradoxical data in which GAP does not alter maximal current amplitude of G protein-activated ion channels, but hastens signaling. The predictions indicate how variations in local concentrations of the component proteins create GTPase-cycle modules with distinctive phenotypes. They provide a quantitative framework for investigating how regulation of local concentrations of components of the GTPase-cycle module affects signaling.
引用
收藏
页码:15899 / 15904
页数:6
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