Fig. 8. Proposed model for GCGR activation and signaling in comparison with β₂AR.

(A) Glucagon binding to GCGR induces conformational change on the extracellular side of the receptor (ECD, TM1, TM2, TM6, and TM7) without inducing outward movement of TM6 on the intracellular side. Coupling of GDP-bound G_s enables TM6 outward movement. The putative high energy required to produce the kinked and outward-moved TM6 may result in slower rates for the receptor-catalyzed nucleotide release of GCGR in comparison with β₂AR. Another rate-limiting step for GCGR-mediated G protein activation is GTP binding to the nucleotide-free G protein that leads to dissociation of the G protein from the receptor. After disengagement of the G protein, relaxation of TM6 to the inactive state is very slow, which might lead to the previously observed prolonged G protein signaling of GCGR in comparison with β₂AR (13). (B) β₂AR activation by an agonist increases the active state population of the receptor with an outward-moved TM6. G_s coupling to β₂AR fully stabilizes the active state and leads to rapid GDP release. The very transient nucleotide-free complex exhibits a high affinity for GTP that readily binds and dissociates the complex. After disengagement of the G protein, β₂AR relaxes back to the more conformational heterogeneous agonist-bound but G protein–free state. (C) Model of the simplified free energy landscapes for GCGR and β₂AR. Shown are the effects of agonist, G protein coupling, and GTP binding to the receptor–G protein complex on the equilibrium between the inactive and active states of the receptors.