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Sticky proteins provide new insight into drug action

t has been known for some time that while epinephrine does increase cyclic AMP in heart cells, it does not activate ion channels. While this situation makes sense because the cell isn't asked to respond in two completely opposite ways, it has not been at all clear how the cell allows one response and suppresses the other.

That likely is because the G proteins activated by epinephrine receptors don't readily dissociate, contrary to the textbook picture. MCG researchers have also shown that at least one other class of G proteins does dissociate, suggesting the textbook picture is at least partly correct.

Why the difference? Previous work on G proteins, including the discovery of the G proteins and their role in signal transduction, was mostly done in test tubes using purified proteins. MCG researchers used a technique they developed to actually look at G protein function inside living human cells.

Their findings suggest that epinephrine interacts with a G protein that doesn't let go of the beta-gamma subunit.

"There was a constant question about how drugs sometimes avoid doing unwanted things," says Dr. Lambert. "This helps us understand how drugs can be specific. The flipside of the coin is some drugs acting on some receptors will have multiple actions because the G proteins do dissociate."

No doubt, the newfound information about G proteins is just one step toward better understanding how hundreds of receptors can act through just four classes of G proteins and produce so many physiologic results. "It's like how can 100 cars drive down four roads and end up in 100 different places," Dr. Lambert says.

But it's a timely piece as science moves toward designer drugs, including some that could actually target G proteins directly, bypassing intermediary receptors, with the hope of getting a more robust response.

In Dr. Lambert's lab, MCG graduate student Gregory J. Digby, first author on the PNAS paper, i
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Contact: Toni Baker
tbaker@mcg.edu
706-721-4421
Medical College of Georgia
14-Nov-2006


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