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Pass the signal. With the binding of its ligand, a cell receptor promotes the release of GDP and the uptake of GTP by the G-protein, thus activating it. Among the protiens then activated by the GTP-binding G-protein is adenylyl cyclase, which converts ATP to cyclic AMP (cAMP), a second messenger. |
G-proteins, the first step in cellular responses to events triggering the release of hormones, provide a link between cell surface receptors and intracellular signaling pathways. These proteins are composed of three subunits: α, β, and γ. To date, 20 human genes have been found to encode different a subunits and, although 10 have been classified into the family, their functions have not yet been determined. Jing Yang and colleagues at the University of Pennsylvania School of Medicine in Philadelphia have been working with , a member of the family, to determine its function in vivo. This protein is primarily expressed in blood platelets and the brain, and it was previously shown to affect various cell receptors and compounds. But because those previous results were based on protein overexpression techniques, s activity in vivo is still in question.
The Philadelphia group developed mice in which the gene for was replaced with one encoding a fluorescent protein, and effects in the central nervous system or platelets were examined both in vitro and in vivo (Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 99849989). appears to play a role in platelet activation by the agonist epinephrine, and platelets from-deficient mice are greatly impaired in their ability to inhibit cyclic adenosine monophosphate formation. However, this did not promote spontaneous or increased bleeding in the mice. Rather, it protected them from blood clot formation when they were injected with otherwise lethal clot-inducing doses of collagen plus epinephrine. This protection was not seen against other platelet-activating or clot-inducing agents. These findings provide vital clues to assist in determining the role of epinephrine in platelet activation.
Behaviorally, the -deficient mice were more sensitive to cocaine, less sensitive to morphine, and completely resistant to the effects of norepinephrine reuptake inhibitors. Together, the results show that preferences exist among receptors for differing members of the family and have demonstrated an in vivo model for studying platelet and antidepressant function.
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