Changing the textbook model: a new signaling process for GPCRs

Researchers at the University of California, San Diego, have discovered a new signaling process involving G protein-coupled receptors (GPCRs), a cellular target that has been utilized by hundreds of different drugs
.
The findings, published in the October 26, 2022 issue of Nature, open up possibilities
for new therapies, including multiple cancers.

GPCRs are the largest and most diverse membrane receptors
in eukaryotes (cells containing nuclei and other organelles).
They inhabit the cell surface, like an inbox, receiving information in the form of sugars, proteins, lipids, and peptides, and play countless roles in bodily functions, including fundamentally regulating communication
between cells.

As such, they have become important therapeutic targets for the treatment of a wide range of conditions, from hypertension to asthma to acid reflux, and their potential in alleviating diseases such as diabetes, obesity and Alzheimer's disease is currently being studied
.
It is estimated that more than one-third of all drugs currently approved by the U.
S.
Food and Drug Administration (FDA) target one or more members
of the GPCR family.

"We believe these new findings may change the textbook model of GPCRs-mediated signaling," said senior study author Jin Zhang, Ph.
D.
, professor of pharmacology, professor of chemistry and biochemistry at UC San Diego School of Medicine and professor of bioengineering at UC San Diego School of Engineering, "which could have profound implications
for future drug development.
" ”

The authoritative view of GPCRs is that they sit on cell membranes and activate a variety of responses, including an enzyme called extracellular signal-regulating kinase (ERK), which triggers cascade signals to control cell growth and survival
.

But Prof.
Zhang's team found that there was essentially no ERK signaling
on the cell membrane.
Instead, GPCRs-mediated ERK signaling originates from endosomes — organelles within cells that sort and help transport substances from the surface to their internal destinations, or help degrade, recycle, and export unwanted substances
.
GPCRs are known to be transported
through endosomes.

ERK signaling regulates the transcription of genes involved in controlling cell growth
.
Dysregulation of ERK signaling is associated with a variety of pathologies, including cancer
.
Therefore, therapeutic interventions targeting members of the ERK signaling pathway are major efforts
of cancer researchers.

Although these receptors play a powerful regulatory role in ERK-related signaling, the mechanism by which GPCRs regulate ERK activation has remained a mystery
.

"We found that GPCRs-mediated ERK signaling, after endosomal activation, propagates into the nucleus, where it turns on important genes to control cell growth," Zhang said
.
"The distance between endosomes and nuclei is closer than the plasma membrane and nucleus, and perhaps the cell uses the three-dimensional spatial organization of cellular organelles and uses 'shortcuts' for efficient receptor signaling
.
"

This finding challenges the paradigm that GPCRs-regulated ERK signaling originates from the cell surface
.
In addition to recent studies showing that active receptors exist within cells, the authors say the data suggest that GPCRs-mediated ERK signaling originates from endosomes
involved in hormone binding and activation receptors.
Previous textbook models have shown that GPCRs can signal through two different molecules: G proteins and inhibitory proteins
.
Blockers are intracellular proteins
involved in terminating plasma membrane signaling.
They play an important role in ERK signaling but are considered scaffolds
that activate ERK.
New research shows greater diversity
in how GPCRs transmit signals downstream.

"Our data strongly support arrestin's involvement in ERK activation, but through its ability to help receptors internalize, rather than act as a scaffold for ERK as previously thought," said co-author Roger Sunahara, Ph.
D.
, a professor
of pharmacology at UC San Diego School of Medicine.

Zhang added that the new study shows that inhibins and G proteins work synergistically to activate ERK on endosomes, with inhibins escorting receptors to endosomes and G proteins recruiting ERK activation mechanisms
.
"Given the large number of GPCRs involved in transmitting various cellular messages to regulate bodily functions, this has broad implications
for both basic science and translational science.
" One immediate implication is the potential generality of the proposed model, which should be studied
outside of the few receptors we studied.
In terms of the impact of translation, the development of GPCR drugs has been influenced by concepts such as 'biased signaling', with drugs developed that preferentially activate G proteins or inhibitory proteins
.
Some receptors require a synergistic effect of inhibitors and G proteins to activate ERK, a discovery that promises to change the way
GPCR drugs are developed.
”

Many types of cancer contain mutations in G proteins, which contribute to cancer development, said J.
Silvio Gutkind, Ph.
D.
, distinguished professor and chair of the Department of Pharmacology at UC San Diego School of Medicine and co-director
of basic science at the Hanna and Mark Lieberman Head and Neck Cancer Center at the UC San Diego Morse Cancer Center.

Many tumors contain persistently active G proteins and GPCRs, including colon, pancreatic, and appendix cancers
.
The new findings can now be used to develop new therapeutic strategies to prevent and treat these human malignancies
.

Co-authors include Kwon Yonghoon, Sohum Mehta, Mary Clark, Geneva Walters, Yanghao Zhong, and Ha Neul Lee, all from UC San Diego
.