Mechanistic hypotheses for the activation of G-protein-coupled receptors

G-protein-coupled receptors (GPCR) play an important role in the functioning of the nervous and endocrine systems. Intensive efforts devoted to mutational analyses of GPCR have greatly enhanced our understanding of the receptor-G-protein signalling pathway. Nonetheless, the lack of receptor structural data mandates that the mechanism of receptor activation can only be probed indirectly through hypothesis testing. Mechanistic models at two different levels, a thermodynamic model and a structural model, are reviewed here. A general thermodynamic model can be used as a framework for analyzing macroscopic experimental data, while a probability function based on a helical-rotation model can potentially provide a link between microscopic conformational changes and macroscopic rate constants and equilibrium constants. Conformational induction and conformational selection are two inseparable consequences of the receptor-binding system. Mechanistic models based on the integration of mutational data, spectroscopic data, and model simulation will form a foundation upon which further experiments can be designed, and consideration of both thermodynamic and structural principles will provide coherent insights into the receptor-activation process.