Regulation of G Protein βγ Signaling

Heterotrimeric guanine nucleotide-binding proteins (G proteins) deliver external signals to the cell interior, upon activation by the external signal stimulated G protein-coupled receptors (GPCRs).While the activated GPCRs control several pathways independently, activated G proteins control the vast majority of cellular and physiological functions, ranging from vision to cardiovascular homeostasis. Activated GPCRs dissociate GαGDPβγ heterotrimer into GαGTP and free Gβγ. Earlier, GαGTP was recognized as the primary signal transducer of the pathway and Gβγ as a passive signaling modality that facilitates the activity of Gα. However, Gβγ later found to regulate more number of pathways than GαGTP does. Once liberated from the heterotrimer, free Gβγ interacts and activates a diverse range of signaling regulators including kinases, lipases, GTPases, and ion channels, and it does not require any posttranslation modifications. Gβγ family consists of 48 members, which show cell- and tissue-specific expressions, and recent reports show that cells employ the subtype diversity in Gβγ to achieve desired signaling outcomes. In addition to activated GPCRs, which induce free Gβγ generation and the rate of GTP hydrolysis in Gα, which sequester Gβγ in the heterotrimer, terminating Gβγ signaling, additional regulatory mechanisms exist to regulate Gβγ activity. In this chapter, we discuss structure and function, subtype diversity and its significance in signaling regulation, effector activation, regulatory mechanisms as well as the disease relevance of Gβγ in eukaryotes.