ReviewRegulation, Signaling, and Physiological Functions of G-Proteins

•Heterotrimeric G-proteins can be regulated by GPCRs and by non-receptor proteins such as Ric-8, G-protein regulator, and regulators of G-protein signaling proteins.•Many proteins interacting with G-proteins have been identified.•G-proteins regulate various physiological functions.•Combinations of structural and computational biological tools can be used to understand the mechanisms of activation of G-proteins by GPCRs and non-GPCR regulators. Multidisciplinary studies are needed to systematically investigate the biochemical mechanisms, cellular effects, and physiological functions in processes involving apparently non-canonical G-protein signaling.

Heterotrimeric guanine-nucleotide-binding regulatory proteins (G-proteins) mainly relay the information from G-protein-coupled receptors (GPCRs) on the plasma membrane to the inside of cells to regulate various biochemical functions. Depending on the targeted cell types, tissues, and organs, these signals modulate diverse physiological functions. The basic schemes of heterotrimeric G-proteins have been outlined. In this review, we briefly summarize what is known about the regulation, signaling, and physiological functions of G-proteins. We then focus on a few less explored areas such as the regulation of G-proteins by non-GPCRs and the physiological functions of G-proteins that cannot be easily explained by the known G-protein signaling pathways. There are new signaling pathways and physiological functions for G-proteins to be discovered and further interrogated. With the advancements in structural and computational biological techniques, we are closer to having a better understanding of how G-proteins are regulated and of the specificity of G-protein interactions with their regulators.

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