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Sticky Proteins Provide New Insight Into Drug Action

How drugs such as adrenalin do primarily one thing – in this case, increase the heart rate – now makes more sense to scientists.//

“Any time you get a sudden jolt, adrenaline (a.k.a. epinephrine) is why your heart rate goes up,” says Dr. Nevin A. Lambert, a biophysicist at the Medical College of Georgia. “If your heart is about to stop and the doctor administers epinephrine, that is what he or she is trying to do.”

New research, to be published in the Nov. 21 print issue of Proceedings of the National Academy of Sciences and already available online in Early Edition, may help explain how cells respond correctly to epinephrine.

Most drugs never get inside cells; they interact with external receptors that activate G proteins roaming inside cells. “If you are going to change the way the cell works, you have to transduce a signal from outside a cell inside,” says Dr. Lambert. “It’s like a relay. G proteins interact with receptors; they run into them, they collide with them. The receptor itself does not do anything other than turn on these G proteins.”

There are only four classes of G proteins, but cells contain thousands of copies of them which interact with hundreds of surface receptors. Each G protein is actually three protein subunits stuck together: alpha, beta and gamma.

Textbooks have long said that once G proteins are activated, the alpha protein splits from the beta and gamma subunits, which are irrevocably stuck together as a beta-gamma pair. Each half of the now dissociated G protein can cause the cell to do something different. “Sometimes they help each other out; sometimes they work at cross purposes,” says Dr. Lambert.

With epinephrine, that should mean the alpha subunit enables production of cyclic AMP, which increases the heart rate, while the beta-gamma pair should activate ion channels, making cells less electrically excitable and decreasing the heart rate.

However, it ha
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