G protein selectivity is regulated by multiple intracellular regions of GPCRs

GTP-binding protein coupled receptors (GPCRs) bind to a vast diversity of extracellular ligands to regulate a wide variety of physiological responses. Upon binding of extracellular ligands, these seven-transmembrane-spanning receptor molecules couple to one or several subtypes of G protein which reside at the intracellular side of the plasma membrane to trigger intracellular signaling events. Amid the large structural diversity at the intracellular regions of GPCRs, there are only 18 different subtypes of G protein belonging to four subfamilies. The question of how GPCRs select and activate a single or multiple G protein subtype(s) has been the topic of intense investigations. This review will attempt to summarize the available data on the structural determinants in GPCRs that regulate the selectivity of G protein activation. The available data suggest that G protein can be activated by structurally diverse cationic alpha-helical structures with no obvious homology in primary sequence. The selectivity of receptor-G protein coupling is maintained by a combination of two functional domains at the intracellular region. One is the 'activation domain' which can activate multiple G protein subtypes, while the other is the 'selectivity domain' which restricts the coupling to the desired signaling pathway(s). A slight change in the conformation at these two functional domains can affect the fidelity of G protein selectivity. This hypothesis can account for the vast structural diversity of GPCRs which link a fascinating variety of extracellular inputs, yet couple to a limited number of intracellular signaling pathways.