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April 13, 2001

Contact: Paul Francuch (312) 966-3457; francuch@uic.edu

COMMON PROTEIN INHIBITS CELL COMMUNICATION

In a finding that has implications for development of new psychoactive drugs, researchers have discovered the place where a subunit of a signaling protein can regulate cell communication with split-second timing.

In a collaborative report published in the April 13 issue of Science magazine, University of Illinois at Chicago associate professor of biological sciences Simon Alford, along with a team of researchers from Northwestern University and the University of Wisconsin-Madison, focused on G proteins, a type of protein that helps cells communicate. G proteins respond to other proteins called receptors, which sit on the surface of cells and wait to detect responses from chemicals that might range from those released by the brain to an odor.

When G proteins respond to receptor activation, they break up and form two subunits, called G alpha and G beta-gamma. Alford focuses on the G beta-gamma.

Nerve cells communicate with one another at specialized structures called synapses, where they release chemical transmitters by a process called exocytosis. G proteins can arrest this process. Alford and his colleagues set out to discover how.

Alford compares exocytosis to a soap bubble within a soap bubble, where the outer bubble is a cell's surface membrane and the inner bubble is a package of chemicals called a vesicule. As the inner bubble touches the outer bubble, it fuses and releases the transmitting chemicals-or neurotransmitters. The process is quick and tightly controlled.

Alford says in the process, a series of proteins on both the vesicule and the outer membrane can send a signal to force the fusing process. "That event can occur in less than 200 microseconds-it goes very fast, but only in response to that signal," says Alford. "The G protein, however, can arrest that process. It can say, even if this very rapid signal occurs, 'you can't release that (chemical) transmitter. I'm telling you not to.'"

The brain quickly makes this determination in response to input from other cells in the body.

"We were able to show the site where the G protein beta-gamma subunit can bind directly to the series of proteins that force exocytosis and prevent it from occurring," says Alford. He says while the process happens quickest in nerve cells, or neurons, it probably also happens in cells throughout the body.

The finding adds another piece to the larger puzzle of how exactly the brain works-something experts say is still a long way from being known. Alford and his colleagues have been working for almost 10 years on the project reported in Science.

Still, the finding could affect development of drugs used to control mood and behavioral patterns. Presently, some psychoactive drugs have receptors that bind to G proteins. Alford's finding may help improve the functioning of these and other drugs.

"This is occurring right now," says Alford. "It's just that, unfortunately, many of the developmental profiles for these drugs, both in academia and in the drug companies, are not very well understood. The more we understand how existing drugs affect these pathways, the more we'll be able to tailor future drugs to more specific areas of the brain."

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