Abstract
Modeling of G-protein-coupled Receptor Signaling Pathways
Highlights
The more we learn about G-protein-coupled receptors (GPCRs) and the pathways they activate, the more complicated our picture of GPCR signaling becomes
Models of GPCR signaling may include vast detail in the G-protein activation/ deactivation cycle [8] or may have no explicit inclusion of G-proteins at all but rather lump their effect into what happens to a downstream component
The pharmacological literature has a rich history in modeling the equilibrium states of GPCRs, models composed of algebraic equations that describe how the addition of ligand and/or G-protein will change the distribution of receptor states [13]
Summary
The more we learn about GPCRs and the pathways they activate, the more complicated our picture of GPCR signaling becomes. At the subsecond to minute time scale, ligand binding, interactions of receptors with G-proteins, G-protein activation/deactivation, and the action of RGS (regulator of G-protein signaling) proteins in GAP or non-GAP roles occur. At a slightly longer time scale, receptor phosphorylation, arrestin binding, and activation of non-G-protein-dependent signaling pathways occur [4, 5]. It is difficult to intuit the net result of so many simultaneous kinetic processes. Add nonlinearities such as feedback, time-varying sequestering of molecules via scaffolds and other mechanisms, and multiple receptor and G-protein. What mechanisms might allow modulation of signaling, desensitization, or receptor cross-talk? With models one can ask questions such as, which of several simultaneous pathways plays a larger role? Do these events happen fast enough to be important in signaling? What mechanisms might allow modulation of signaling, desensitization, or receptor cross-talk? What factors influence ligand efficacy? Interruption of processes at which points (i.e. drug targets) is most effective? Which experimental protocol is most likely to emphasize a particular mechanism?
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