Researchers at University of California San Diego have identified a new signaling process involving G protein-coupled receptors (GPCRs), a cellular target already exploited by hundreds of diverse drugs. The discovery, published in the October 26, 2022 issue of Nature, opens the possibility of new therapies, including for multiple forms of cancer.
GPCRs are the largest and most diverse group of membrane receptors in eukaryotes — cells containing a nucleus and other organelles. Residing on the cell’s surface, they act as an inbox for messages arriving in the form of sugars, proteins, lipids and peptides, and play myriad roles in body functions, including fundamentally in regulating communications between cells.
As a result, they have become an important therapeutic target for treating everything from high blood pressure to asthma to acid reflux, with ongoing investigations of their potential in moderating conditions like diabetes, obesity and Alzheimer’s disease. It is estimated that more than one-third of all current Food and Drug Administration-approved drugs target one or more members of the GPCR family.
“We believe these new findings may change the textbook model of GPCR-mediated signaling,” said senior study author Jin Zhang, PhD, professor of Pharmacology at UC San Diego School of Medicine, professor of Chemistry and Biochemistry, and professor of Bioengineering at UC San Diego Jacobs of Engineering, “and that could have profound implications for future drug development.”
The canonical view of GPCRs is that they sit on the cell membrane where they activate a variety of reactions, including an enzyme called extracellular-signal-regulated kinase (ERK), which triggers a cascade of signals to control cell growth and survival.
But Zhang’s team found that there is essentially no ERK signaling at the cell plasma membrane. Rather, GPCR-mediated ERK signaling originates at the endosomes — organelles within the cell that sort and help deliver material from the surface to internal destinations or help degrade, recycle and export unneeded material. GPCRs are known to be transported through endosomes.
Source: Read Full Article