July 30, 2004

Study finds receptor cycling important for signaling

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Qin Wang, Ph.D., left, and Lee Limbird, Ph.D., discovered a new regulatory mechanism for cell signaling. Photo by Anne Rayner.

Study finds receptor cycling important for signaling

Lee E. Limbird, Ph.D., professor of Pharmacology, likens her laboratory’s latest scientific findings to a Tide commercial.

“You bring in that dirty shirt, get it washed, put it back on and run out to play again,” she said.

The receptors Limbird studies are like the dirty shirt — once activated, they have to go inside the cell and get cleaned up before returning to the cell surface to receive another signal.

Limbird and colleagues including Qin Wang, Ph.D., research assistant professor of Pharmacology, detailed their findings of a new regulatory mechanism for cell signaling in a recent issue of Science. They showed how a protein called spinophilin opposes the actions of a well-studied protein called arrestin.

“We think of spinophilin as arrestin’s nemesis,” Limbird said.

Thousands of different receptors interact with arrestin, and at least 60 percent of available drugs target these receptors, she added, giving the findings broad implications for pharmaceutical development.

The studies stand a decade’s worth of research on end. Arrestin was originally identified — and named — as a molecule that turned off receptor signaling.

“Ten years of research has focused on the mechanisms of turnoff,” Limbird said, “but when we asked the role of this molecule in vivo, it was in fact to enhance the sensitivity of the system.”

Arrestin does turn off the receptor signal, she said. But it also facilitates the movement of the receptor inside the cell, where the receptor can get “buffed up, refreshed, and back out on the front line again” — like that dirty shirt in the Tide commercial.

“What’s important about arrestin is its involvement in re-booting the receptor,” Limbird said. “It’s a cycle; it’s not an on-off switch.”

This mechanism is especially important for the rapid-fire signaling of the nervous system, said Wang, the lead author of the Science paper.

The findings represent another example of how the cell maintains balance. Spinophilin and arrestin act as “point-counterpoint molecules” to fine-tune cell signaling, Limbird said. And they offer a fresh level for potential intervention.

“Targeting the receptor alone (with drugs) may not be useful, but if you could also target the point-counterpoint molecules, you might be able to make the interventions more disease specific,” Limbird said.

Other authors of the Science article include Jiali Zhao and Ashley Brady at Vanderbilt, Jian Feng at the State University of New York at Buffalo, Patrick Allen at Yale University, Robert Lefkowitz at Duke University, and Paul Greengard at The Rockefeller University. The research was supported by the National Institutes of Health and the Howard Hughes Medical Institute.