Re-examining the 'Dissociation Model' of G protein activation from the perspective of Gβγ signaling.

G protein-coupled receptors (GPCRs) represent a major group of drug targets with tremendous pharmacological value. Signals arising from GPCRs are primarily transduced via two functional components of their corresponding G proteins, the Gα subunit and the Gβγ dimer that dissociate from each other upon activation of the heterotrimer (Gαβγ). The Gβγ dimer has become an increasingly popular subject in GPCR signaling, owing to its numerous effectors and notable roles in signal integration. Because Gβγ dimers participate in a wide range of intracellular processes that regulate cellular physiology, they are often implicated in the pathology of various diseases. Yet, one caveat to the current 'Dissociation Model' on GPCR signaling is that unequivocal Gβγ signals are biasedly detected with Gi/o -coupled receptors, while Gβγ signals from Gs - or Gq -coupled receptors seem to play an auxiliary role. In this review, we revisit the evidence for or against the 'Dissociation Model' and discuss in detail several hypotheses that may explain such disparity and provide alternative interpretations to accommodate the 'biased Gβγ signals' observed in different biological systems. The issue of whether unique combinations of Gβγ dimer can confer signaling specificity is also discussed in the context of physiological relevance.