Nobel Prize work on G-protein-coupled receptors paves way for drug discoveries

Brian Kobilka

Brian Kobilka, MD, of Stanford University School of Medicine and Robert Lefkowitz, MD, of Duke University Medical Center have won the 2012 Nobel Prize in Chemistry "for studies of G-protein coupled receptors."

But what is a G-protein-coupled receptor?

These receptors play an essential role in transmitting messages into our cells, including signals from neurotransmitters (such as adrenaline and dopamine), hormones (such as follicle stimulating hormone, which helps control ovulation), and even light in our eyes and smell molecules in our noses.

Made of protein, the receptors, known as GPCRs, sit embedded in the cell membrane, with a portion sticking out on each side of the membrane. On the exterior side, the receptor forms a small trench in the membrane that can bind to a specific signal, such as a hormone or neurotransmitter.

The interior side of each of these receptors is like a small factory. When a signal binds the outside of the receptor, the whole receptor changes shape and the factory inside the cell switches on. The factory makes many new signal molecules, which travel to different parts of the cell's interior and amplify the original signal.

Early in his career, Lefkowitz, professor of medicine and of biochemistry at Duke, did work on these receptors, including studies using radioactivity to understand the receptors' function and their shape in the cell wall. Some of his early work focused on the beta-adrenergic receptor, which responds to adrenaline.

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Kobilka led a team that published a 2011 paper in Nature describing the structure of the beta2 adrenergic receptor, a type of G-protein coupled receptor, bound to the molecule that activates it outside the cell and to the G proteins it cooperates with inside the cell. The diagram, adapted from that publication, shows the activator molecule in magenta, the receptor in red, and three G proteins in green, turquoise and yellow. The red receptor segments sit embedded in the cell membrane, which is not shown in this diagram.

Kobilka, who is professor and chair of molecular and cellular physiology at Stanford, began working with Lefkowitz in the 1980s, and his first major contribution was to isolate the gene that codes for the b-adrenergic receptor. This research helped the scientists realize that g-protein receptors are a large family, with many different examples throughout the body. When the human genome was sequenced, it revealed that humans have about 800 different G-protein-coupled receptors, including many whose function is still not understood.

Not only are G-protein-coupled receptors important for normal function of most of our body's cells, they are also the targets for about 40 percent of drugs. The drugs that use G-protein-coupled receptors include Zyprexa, which is used to treat schizophrenia; the antihistamine Clarinex; and Zantac, which is used for stomach ulcers and gastro-esophageal reflux disease. G-protein-coupled receptors are also involved in some kinds of drug addictions, such as addiction to morphine and other opiates.

"Orphan" g-protein coupled receptors, those with unknown functions, are considered potential targets for new drugs and many are the subject of active drug-design research.



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