Heterotrimeric G protein signaling outside the realm of seven transmembrane domain receptors.

Heterotrimeric G proteins, consisting of the guanine nucleotide-binding Galpha subunits with GTPase activity and the closely associated Gbeta and Ggamma subunits, are important signaling components for receptors with seven transmembrane domains (7TMRs). These receptors, also termed G protein-coupled receptors (GPCRs), act as guanine nucleotide exchange factors upon agonist stimulation. There is now accumulating evidence for noncanonical functions of heterotrimeric G proteins independent of 7TMR coupling. Galpha proteins belonging to all 4 subfamilies, including G(s), G(i), G(q), and G(12) are found to play important roles in receptor tyrosine kinase signaling, regulation of oxidant production, development, and cell migration, through physical and functional interaction with proteins other than 7TMRs. Association of Galpha with non-7TMR proteins also facilitates presentation of these G proteins to specific cellular microdomains. This Minireview aims to summarize our current understanding of the noncanonical roles of Galpha proteins in cell signaling and to discuss unresolved issues including regulation of Galpha activation by proteins other than the 7TMRs.