Assessing the functionality of g protein-coupled receptor oligomerization with mathematical modeling.

Resumo

G protein-coupled receptors (GPCRs) are seven-transmembrane helix proteins which have been widely investigated because of their involvement in a great variety of physiological functions. Emerging properties of GPCRs such as oligomerization, crosstalk, dosage-dependent switch or functional selectivity are challenging traditional concepts of molecular pharmacology. New terms are appearing and classical definitions need to be revisited. The classical receptor activation hypothesis -one receptor, one G-protein, one effector pathway- seems to be no longer valid and a high-dimensional and dynamic space is becoming the new paradigm. The increasing complexity of signal transduction mechanisms hampers the analysis of functional data but, on the other hand, it may ultimately provide opportunities to more effectively modulate the cell signaling process. Thus, the new knowledge has the potential to foster the development of new drugs with adequate functional profiles to alleviate pathological situations. The goal of the present work was to construct mathematical models which include the newly discovered features that can affect the function of the GPCRs. A parsimonious approach was followed when constructing the models. Thus, experimental data could be fitted and changes in the parameter values could be tracked. In pharmacology, mechanistic models result from applying the law of mass action to the reaction paths of the process under study. Hence, the parameters of these models have straight relation with the biological process involved. The models were used, in particular, to explore receptor homooligomerization in conjunction with concepts such as cooperativity or allosteric modulation among others. An accurate evaluation of the models together with the simulations performed provided new insight into the functional implications of this phenomenon. As a general conclusion, it may be stated that our models suggest a direct involvement of receptor homooligomerization with the receptor function instead of merely playing a role in receptor trafficking or a quality control for misfolded proteins. Indeed, it can affect the membrane organization and dynamics of the receptors, the fine tuning of the signal transduction or even the activation of diverse signaling pathways depending on ligand concentration. The consequences of this phenomenon will be thoroughly analyzed and discussed in the present piece of work.