Metabotropic GABA_B Receptor Activation Induced by G Protein Coupling

G protein-coupled receptors (GPCRs) play central roles in regulating cellular responses through heterotrimeric G proteins (GP). Extensive studies have elucidated the complex cellular signaling mediated by GPCRs that accompany dynamic conformational changes upon activation. However, there has been less focus on the role of the GP on the activation process, particularly for class C GPCRs that function as obligate dimers. Herein, we report the pivotal role of GP coupling on the dynamic activation process for the metabotropic γ-aminobutyric acid receptor (GABA_BR) based on extensive atomistic simulations. We find that GP coupling triggers drastic conformational changes in the GABA_BR transmembrane domain (TMD), while an agonist alone is insufficient to shift the equilibrium state from the inactive to the active states. These conformational changes induced by GP coupling destabilize the inactive TM5/TM5 interface, shifting the equilibrium toward the activated TM6/TM6 interface. This active role of the GP in activation provides fresh insights into the activation mechanism of GABA_BR and perhaps other class C GPCRs. These insights should aid in the development of more potent and selective drugs.