UPenn protein study

September 04, 2000

One protein is linked both to blood-clotting and response to drugs, penn researchers find

A possible prelude to more effective pain-killers, anti-depressants and clot-busters, the research also sheds light on human drug dependency

The common protein Gz may wield surprising power over the body's brain and bloodstream, supporting the body's ability to stave off lethal blood clots and the brain's ability to avoid strokes. It is also involved in responses to psychoactive such as cocaine and morphine.

These findings appear in a study by researchers at the University of Pennsylvania School of Medicine that appears in the September issue of the Proceedings of the National Academy of Sciences.

Although the findings have been identified only in animal studies, the information holds promise for the future development of preventive treatments for thrombotic diseases such as strokes and heart disease, according to Jing Yang, PhD., the principal author of the study. Yang is an instructor in the Pharmacology Department and the Center for Experimental Therapeutics at Penn's School of Medicine.

A two-fold research effort involving both mouse cells and living animals, the research establishes a direct link between the Gz protein and the normal functioning of the body's central nervous system. It also demonstrates that the protein must be present for the formation of blood clots even after chemicals designed to induce clotting have been introduced into the bloodstream.

Scientists have long understood that the Gz protein mediates the work and effectiveness of cell receptors, influencing the way the cells experience and interact with their environment. But until the Penn study, they had not established what, exactly, that influence might be.

The Penn investigation was initiated by Lawrence F. Brass, MD, PhD, professor of medicine and pharmacology at Penn.

As a hematologist, Brass began the study because he was primarily interested in determining what activates platelets.

Over the course of two years, the researchers in his laboratory "designed" and studied a strain of mice lacking the Gz protein, enabling them to conduct simultaneous research on the animals' blood systems and brain activities.

"Our long-range goal is to understand what can be done to prevent platelets from being activated in the area of an injury. But at the same time, the research also helps us understand what's involved when people abuse psychoactive drugs such as cocaine and morphine," Brass said.

"It's a step to understanding how to make better pain-killers for people suffering intractable pain," he said. "Understanding this stuff is not a trivial intellectual exercise."

The researchers found, for instance, that in the animals the Gz protein conveys signals from epinephrine -- a hormone that stimulates the nervous system and accelerates the heart rate and enhances blood-clotting.

In the study, the specialized animals' response to cocaine was increased, although their response to morphine was reduced, Yang said.

Even more significantly, when the mice were administered drugs from the series of anti-depressants known as catecholamine reuptake inhibitors (desipramine, and reboxetine), "they didn't respond at all," she said.

"We don't have data for humans yet, but the basic mechanism may be the same in both human and mice models," Yang said. "What we can do is conduct some biochemical and pharmacological studies, to see whether the slight variations that exist will affect the influence of the protein. If the same thing is true for humans, it opens up a whole new field for the discovery of new drugs."
The brain studies were performed in collaboration with Julie Blendy, PhD and Irwin Lucki, MD, PhD, professor of psychiatry. Other researchers who participated in the study include: David Manning, PhD., Professor of Pharmacology; Mortimer Poncz,MD., Professor of Pediatrics; Jie Wu, research specialist in the Department of Medicine; M. Anna Kowalska, PhD., instructor in Pediatrics; Ashutosh Dalvi, PhD., postdoctoral fellow in Psychiatry, and University of Pennsylvania graduate students Nicolas Prevost and Peter J. O'Brien.

The research was funded by the National Institutes of Health.

Editor's note: Dr. Yang may be reached directly at: 215-573-3541.

University of Pennsylvania School of Medicine

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