Turning It On: How G Proteins Communicate in the Cell

During a summer hike in the Cascades, you are strolling along when suddenly, around the bend, you spy a huge grizzly bear. Your body goes on red alert. Instantly adrenaline is pumped throughout your blood system, prompting your liver and muscles to release energy-producing glucose. Your heart beats quickly, your lungs breathe faster, and you are ready to run as fast as you ever have in your entire life.

At this particular moment, you may not be wondering how this all works inside your cells, but it's been a question for scientists since hormones were first isolated. In the early part of this century, scientists knew that a hormone, such as adrenaline, would signal a response in the cell--"release glucose into the blood." But how exactly that message was translated through the cell wall was unclear--at the time they thought it worked in one turn, like a lock and key.

But the Nobel-prize winning work of Martin Rodbell proved that there is a lot more going on--a series of switches have to be thrown chemically in order for the message to get passed along. A key to those chemical switches are G proteins.

And if something is wrong with this process, such as leaving the switch "on" or "off" for too long, there is trouble. Scientists now know that cholera alters the G proteins, leaving the switch "on" for too long, which prevents the normal absorption of salt and water in the intestines--leading to dehydration or even death.

Diabetes and alcoholism are thought to be caused, in part, by G protein malfunction, and scientists have also traced a form of pituitary cancer to impaired G proteins. While G protein research has not yet let to a miracle cure, the discovery may lead to eventual treatments.

The system itself is a complex series of reactions. When you see the bear in the woods, your adrenal gland releases adrenaline. The hormone races throughout your body, but only the cells that need the signal, such as your heart muscle, have the receptors that can detect it. The hormone molecule "tickles one of the receptor outside the cell wall, and inside the wall, the other end giggles," explains Rodbell's NIH colleague Constantine Londos.

The "giggling" side of the receptor changes its shape, turning into an irresistible docking site for a G protein. Once snuggled into its site, the G protein itself undergoes a change. It had been holding on to a molecule called GDP. Now it releases that and grabs onto a related molecule called GTP.

But that's not the end of the transformation. With GTP in its grasp, the G protein now works on other membrane processes, such as enzymes and ion channels. These enzymes can now make a new messenger molecule, called cyclic AMP. What follows is an "enzymatic cascade," where the cyclic AMP causes a protein reaction. In the case of your liver and muscles responding to the sight of the grizzly, the enzymes release glucose from the cells, giving you the energy to run away.

The part G proteins play in the communication process happens in a instant. As you turn and run, all you can hope is that the grizzly's G proteins aren't working as well as your own.--Tom Griffin

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