Understanding the ternary complex between G protein-coupled receptors (GPCRs), cognate G proteins, and their ligands is an important landmark for drug discovery. Yet, little is known about the specific interactions between GPCRs and G proteins. For a better perspective on the ternary complex dynamics, we adapted a β₂-adrenergic receptor(β₂AR)–tetGs_α reconstitution system and found evidence that for efficient coupling of the β₂AR to Gs does not require specific interactions between the βγ-subunits and the β₂AR. Our results demonstrate that specific interactions between βγ and the β₂AR are not required for G protein activation but likely serve to anchor Gs_α to the plasma membrane. Our results also suggests that the advantages of analysis of G protein activation by using β₂AR receptor–tetGs_α system in vitro at the close proximity of the receptor may constitute a simple screening system that avoids false positives and potentially adapted to screen drugs for other GPCRs.