Subtype-dependent regulation of Gβγ signalling

G protein-coupled receptors (GPCRs) transmit information to the cell interior by transducing external signals to heterotrimeric G protein subunits, Gα and Gβγ subunits, localized on the inner leaflet of the plasma membrane. Though the initial focus was mainly on Gα-mediated events, Gβγ subunits were later identified as major contributors to GPCR-G protein signalling. A broad functional array of Gβγ signalling has recently been attributed to Gβ and Gγ subtype diversity, comprising 5 Gβ and 12 Gγ subtypes, respectively. In addition to displaying selectivity towards each other to form the Gβγ dimer, numerous studies have identified preferences of distinct Gβγ combinations for specific GPCRs, Gα subtypes and effector molecules. Importantly, Gβ and Gγ subtype-dependent regulation of downstream effectors, representing a diverse range of signalling pathways and physiological functions have been found. Here, we review the literature on the repercussions of Gβ and Gγ subtype diversity on direct and indirect regulation of GPCR/G protein signalling events and their physiological outcomes. Our discussion additionally provides perspective in understanding the intricacies underlying molecular regulation of subtype-specific roles of Gβγ signalling and associated diseases.