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Dual Role Found for Key Cell Signaling Regulator Involved in Major Body Functions

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Duke Health News 919-660-1306

DURHAM, N.C. -- In an unexpected finding, researchers at Duke University Medical Center report demonstrating that a class of proteins known to halt cellular responses to hormones and other stimuli also play a role in reestablishing responsiveness. The proteins, called ß-arrestins, are involved in a universal signaling mechanism known to regulate processes including sight, smell, taste, heart rate and brain function.

The findings, published in the Jan. 19 issue of the journal Science, open new avenues for understanding the mechanisms underlying the reestablishment of cellular responsiveness for hormones and other stimuli, the researchers said. They said such advances may provide novel strategies for the treatment of diseases such as hyperthyroidism, Parkinson's disease, asthma, and congestive heart failure, which are caused by malfunctions in the G protein-coupled receptor signaling system.

The research was supported by the National Institutes of Health and an unrestricted neuroscience award from Bristol Myers Squibb.

"Any time we discover a second essential function associated with an important protein, the chances of being able to identify disease-causing mutations in that protein are much more likely," said Marc Caron, the study's principal investigator, a Howard Hughes Medical Institute investigator, and professor of cell biology at Duke. "Mutations limiting the desensitization function of ß-arrestins would be expected to lead to an exaggerated response to stimuli. On the other hand, a mutation or drug that interferes with the resensitization function of ß-arrestins would be expected to cause irreversible desensitization."

When the body receives stimuli from its environment, such as light, odors, or hormones, a class of proteins called G protein-coupled receptors on the cell's surface recognize these cues and help translate that information into chemical messages that determine how a particular cell responds to a given stimulus. Once the information has been transmitted, the receptors are quickly shut off by a process called desensitization. But this process must also be reversed, or cells would not be able to respond to these signals the next time they are encountered. Scientists said it now appears ß-arrestins play a major role in both desensitization and resensitization.

"G protein-coupled receptors control many aspects of our daily life and the desensitization mechanism plays an important role in regulating responses to our environment," Caron said . "We can all relate to the experience of entering a bakery and inhaling the satisfying aroma of freshly baked bread. But we become desensitized to that smell, and within a few minutes we are hardly aware of it. Without the counter-balancing resensitization mechanism in our olfactory cells, we could not experience the pleasant smell of a bakery again for a much longer time."

G protein-coupled receptor mechanisms are pervasive in nature and are found in organisms from slime-mold and yeast to every cell of the human body. The mechanism to turn off responses to stimuli is just as universal and controls the duration and intensity of the body's response to environmental stimuli and internal responses to hormones. Desensitization also limits the effectiveness of drug therapy that targets G protein-coupled receptors, such as drugs to treat asthma.

Prior to this finding, researchers knew that the desensitization mechanism involves the addition of a phosphate to the receptor by a class of enzymes called G protein-coupled receptor kinases. The phosphate provides an anchor for the ß-arrestins, which then attach to and shut off the receptor. However, the mechanism by which the cell is resensitized has been poorly understood. The Duke research team study shows that ß-arrestins target receptors for removal from the cell surface to the interior of the cell, where phosphate is removed and recycled to the cell surface as functional receptors.

"Our findings are exciting because we have found an unsuspected new activity for an important component of this widely used signaling pathway," said Stephen Ferguson, lead author of the article and researcher in the department of cell biology. "This work shows the ability of ß-arrestins to turn off receptors is distinct from its newly discovered role in reestablishing cellular responsiveness."

The research team is particularly interested in how these signaling mechanisms control the action of the neurotransmitter dopamine in the brain and pituitary gland. Research in Caron's lab and other laboratories suggests malfunctioning dopamine responsiveness in brain cells contributes to schizophrenia, Parkinson's disease, and other disorders. Armed with this new knowledge, Caron said he plans to explore how ß-arrestins coordinate their activities and the consequences to the cell when they are not doing their job

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