Thematic series on the
cell biology of GPCR signaling

G-protein coupled receptors, known for short as GPCRs, are the main conduit for cells to interact with their environments. The Journal of Biological Chemistry recently published a collection of minireviews examining the current state of GPCR research. These reviews cover new technology for studying GPCR activation and novel signaling methods that call into question conventional GPCR wisdom.

All GPCRs share the same basic architecture: an extracellular N-terminus, seven transmembrane spanning segments and an intracellular C-terminus. More than 1,000 genes encode GPCRs in the human genome. This large family is responsible for detecting an enormous range of extracellular stimuli, from photons to hormones to peptides.

Once a ligand becomes bound by a GPCR, the receptor undergoes a conformational change and activates the heterotrimeric G-proteins (α, β and γ.) The G-proteins then activate downstream pathways corresponding to the initial stimuli. Signaling is attenuated through proteins that promote reassociation of the heterotrimeric G-proteins or through endocytosis of an activated receptor. The entire G-protein cycle occurs on a millisecond timescale and is consequently an efficient way to translate environmental information to an appropriate cellular response.

Henrik G. Dohlman of the University of North Carolina at Chapel Hill, a JBC associate editor, organized the recent JBC series. “G proteins are extremely important in pharmacology and physiology and are among the best-studied proteins in the cell,” says Dohlman. “Even after nearly half a century of investigation, they continue to be a source of new knowledge and more than a few surprises.”

The first JBC review, by Terri Clister, Sohum Mehta and Jin Zhang of Johns Hopkins University School of Medicine, is titled “Single-cell analysis of G-protein signal transduction.” The authors discuss the use of FRET in probing GPCR activation. FRET pairs can be attached to a receptor to gauge the conformational changes or to the heterotrimeric proteins to assess receptor and G-protein interactions. The group also introduces optogenetics, which uses modified GPCRs that can be activated by a specific wavelength of light, leading to both spatial and temporal regulation of GPCR signaling.

In the second review, “GPCR signaling via heterotrimeric G proteins from endosomes,” Nikoleta G. Tsvetanova at University of California, San Fransisco, and others detail how GPCRs are able to signal after endocytosis. GPCRs originally were believed to signal exclusively from the plasma membrane; upon receptor endocytosis, the signaling ceased. However, recent biochemical studies and live-imaging have shown that receptors continue to activate Gα following internalization. While it is unclear if GPCR signaling in the endosome occurs in vivo, this phenomenon represents a new compartmental component to GPCR signaling.

The final review, written by Mikel Garcia-Marcos at Boston University School of Medicine and others, is entitled “GIV/Girdin transmits signals from multiple receptors by triggering trimeric G protein activation.” GIV is a unique protein that acts as a platform between GPCR signaling and other signaling cascades. Following an interaction with an activated receptor tyrosine kinase, GIV is able to act as a GEF for Gα. Consequently, G-protein activation occurs in the absence of an activated GPCR. This mechanism of G-protein activation has important implications for understanding hyperactive G-protein signaling.

Caitlin Hanlon Caitlin Hanlon earned a bachelor’s degree from Ursinus College and is pursuing a Ph.D. in the the Johns Hopkins School of Medicine cell biology department.