New Protein Discovery may Widen Drug Design Options

An important family of proteins known to function at the cell surface also functions at a site within the cell, say researchers.

The findings by researchers at the University of North Carolina at Chapel Hill have potential implications for drug development because they involve G protein-coupled receptors (GPCRs), which are the target of 40 to 50 per cent of modern medicinal drugs—such as antihistamines and drugs for high blood pressure.

In humans, reactions to everything from taste and smell to stimulants like adrenaline or caffeine requires G-protein signalling.

So far, the only known way to turn on a G-protein was through a receptor sitting on a cell’s surface membrane, which accepts outside signals and relays them inside the cell.

Henrik Dohlman, a professor of Biochemistry and Biophysics, believes that discovering a protein that activates G-proteins from inside a cell may open up an entirely new pathway for drug development.

“No drug is 100 percent effective, 100 percent free of side effects and 100 percent safe. 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,” said Dohlman, senior author of the study published online in the journal Current Biology

Mike Lee, a graduate student in the UNC School of Medicine’s department of pharmacology, identified the new protein called Arr4 in yeast cells. He employed a mutant form of G-protein to search for any messengers inside the yeast cell with an affinity for G-proteins.

“We went looking for things that could activate G-proteins but don’t resemble known receptors,” Lee said.

He identified seven proteins that weren’t receptors, but did bind to G-proteins.

The researcher then moved on to carry out further tests on one of the seven proteins, Arr4, to determine its function.

He found that in yeast, Arr4 was involved in cell fusion, a process in which two yeasts fuse together to form one cell by combining their genetic data.

While a G-protein coupled receptor (GPCR) controls cell fusion, Arr4 appears to play a supporting role, Lee says.

According to him, Arr4 may allow the cell to go through several additional rounds of signal activation without needing to go back to the receptor.

“Our current thinking is it’s not so much that this is the ignition for signaling, it’s more like an overdrive. Once the pathway is activated by the hormone outside, Arr4 sustains the activity inside. What we don’t know is if Arr4 is itself simulated by some signal, and of course we’re very interested in finding out if that’s the case,” Lee said.

Source-ANI
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