GPCR Signaling. GPCRs display an extensive variety of structural domains, respond to a diverse assortment of ligands, and induce diverging and complex intracellular signaling cascades, however all GPCRs share a common mechanism for transducing signals across the plasma membrane. As their name implies, G protein-coupled receptors interact with intracellular heterotrimeric guanine- nucleotide-binding regulatory proteins (G proteins), which serve as mediators of GPCR activation. G protein complexes are composed of three subunits, α, β, and γ. Upon ligand binding, GPCRs shift into a favorable conformation for G protein binding, this conformational change promotes the release of bound guanosine diphosphate (GDP) from the G protein α-subunit (Gα) allowing guanosine triphosphate (GTP) to bind. Exchange of GDP for GTP is driven by a high intracellular concentration of GTP (XxXxx et al. 1999). GTP binding leads to a conformational change of Gα, causing dissociation of the β/γ subunit which in turn allows both functional subunits to associate with and modulate the activity of downstream effectors (Xxxxxx 1987; Xxxxxxx and Xxxxxxxx 2016). Each G-protein subunit exists in multiple forms. Assembly of different combinations of G protein subunits into heterotrimers can result in distinct intracellular changes. Humans have 15 different types of Gα, which are commonly grouped into four categories, Gs, Gi, Gq and G12 (Pierce, Premont, and Xxxxxxxxx 2002; Syrovatkina et al. 2016). The Gs family of receptors contains Gαs and Gαolf. Gαs is ubiquitously expressed whereas Gαolf is mostly restricted to olfactory neurons. Depending on the type of G protein to which the receptor is coupled, a variety of downstream signaling pathways can be activated. Coupling of Gαs family members stimulates adenylyl cyclase, leading to an increase in cAMP which in turn activates protein kinase A (PKA), a serine/threonine kinase with diverse cellular functions, and in some cells can activate cAMP-gated ion channels (Xxxxx and Xxxxxxx 2002) and exchange factor directly activated by cAMP (EPAC) proteins. The Gi family is the largest and most diverse family, it includes Gαi1-3, Gαo, Gαt, Gαg, and Gαz. Gαi proteins are found in most cell types, while Gαo is predominantly expressed in the brain. Gαt and Gαg mediate sensory information and are found in visual and taste receptor cells, respectively. Gαz is expressed in the brain and in platelet cells. Contrary to Gαs-mediated signaling, Gαi family members inhibit adenyly...
