UNC going into overdrive

Discovery of “overdrive” GPCRs that function within cells may broaden drug design options

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CHAPEL HILL, N.C.—The importance of G protein-coupled receptors (GPCRs) is well-known to drug discovery and development folks, given that such molecules are the target of as many as half of modern pharmaceuticals, such as antihistamines and antihypertension drugs. But now, researchers at the University of North Carolina at Chapel Hill have discovered a subset of GPCRs that could add a new wrinkle in drug design efforts.

Up to now, the only known way to turn on a G-protein was through receptors that lay on the surface of cells. But the UNC scientists found that GPCRs can also function from sites within cells—and discovering a protein that activates G-proteins from inside a cell could open up an entirely new pathway for drug development, according to Dr. Henrik Dohlman, a professor of biochemistry and biophysics in UNC's School of Medicine and senior author of the findings of the recent study into GPCRs, published in the Feb. 14 issue of the journal Current Biology as well as in the online version of the journal.

"No drug is 100 percent effective, 100 percent free of side effects and 100 percent safe," he notes. "The more options we have biochemically, the more selective we can be in designing new drugs. If we can find another way of modulating G-proteins, we could expand the drug targets that are available to pharmacology."

In the study, the UNC team identified seven proteins that weren't receptors, but did bind to G-proteins, and did further tests on one of the seven proteins, Arr4, to determine its function. In yeast, Arr4 is involved in cell fusion, and a GPCR controls cell fusion, while Arr4 appears to play a supporting role.

"Our current thinking is it's not so much that this is the ignition for signaling; it's more like an overdrive," says Mike Lee, a graduate student in the university's department of pharmacology, who identified Arr4. "Once the pathway is activated by the hormone outside, Arr4 sustains the activity inside. What we don't know is if Arr4 is itself stimulated by some signal, and of course we're very interested in finding out if that's the case."

According to Dohlman, this work came out of a long-standing interest in finding pathway modulators that could serve as future drug targets. He cites RGS proteins as an early success in such efforts—proteins that act in opposition to receptors to inhibit G protein signaling.

"Notably, RGS proteins were discovered in yeast," Dohlman notes. "Yeast have a GPCR and G protein, very similar to those in humans. However yeast also provides enormous advantages for doing large-scale genomic and proteomic analysis, including identification of pathway regulators. If a new regulator can be identified in yeast, there is a good bet that it also exists in humans.
That was the case for RGS proteins, and I expect there is something like Arr4 will eventually be found in people as well."

The real practical benefits are still years or decades away, Dohlman admits, but he believes the benefits will lead to real successes.

"I have been working on GPCRs since my days as a graduate student working on receptors for epinephrine. These 'adrenergic receptors' recognize a variety of drugs, including albuterol for asthma, and beta-blockers for the treatment of hypertension," he points out. "Other drugs work on G protein pathways indirectly, in some cases boosting the response to endogenous neurotransmitters."

A good example, he says, are selective serotonin reuptake inhibitors, which are used in the treatment of depression and anxiety. SSRIs work by inhibiting reuptake of the neurotransmitter serotonin into the presynaptic cell, increasing the level of serotonin available to bind and stimulate the post-synaptic receptor.

"Thus SSRIs stimulate receptor function indirectly, or to use the analogy, put them into 'overdrive'," he says. "So proteins analogous to Arr4 could hypothetically be targeted for the treatment of depression or asthma."

One of the hurdles to overcome is the fact that targeting proteins inside cells is far more challenging that getting drugs to a cell's outer membrane.

"There is of course precedent for drugs that do this—all steroids for example—but it is a hurdle to overcome," Dohlman says.

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