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It takes a billion brain cells, a little electricity, and a molecule that resembles a shellfish to read this sentence. The clam-like molecule, which is a type of glutamate receptor, helps create most of the electrical signals that send information from one brain cell to another.

But despite the preeminence of glutamate receptors in generating electrical signals that let you read and remember where you left your keys, researchers are just beginning to understand what the receptors look like and how they work.

In his latest work on AMPA-type glutamate receptors, Dr. Eric Gouaux, professor of biochemistry and molecular biophysics in P&S, has elucidated how the receptor shuts down, a finding that is important in determining how the receptor becomes reactivated to function again. This new structural view will help researchers better understand how the receptor affects learning and memory, and may lead to improved drugs to treat conditions associated with the receptors, such as Alzheimer's disease, Parkinson's disease, and stroke.

Glutamate receptors, comprised of four subunits, are protein molecules that traverse the membrane of nerve cells and initiate electrical signals when they bind the neurotransmitter glutamate. Binding opens an ion channel in the receptor, allowing ions to flow into the neuron and create an electrical signal that enables communication between nerve cells. Within milliseconds, as glutamate binds to the receptor, the ion channels close, ending communication between nerve cells for hundreds of milliseconds. If the channel closes quickly, though, less information is sent. If the channel stays open a little longer, more information is sent. Quick closure may be occurring in neurodegenerative diseases. After glutamate falls off the receptor, the receptor becomes ready for the next cycle of binding, ion flow, shut down, and reactivation.

Dr. Gouaux's work on the channel, published in the May 16 issue of Nature, used a combination of X-ray crystallography and electrical measurements of ion flow and described how the receptor stops letting sodium ions into the channel and prevents the channel from immediately opening again in a process called desensitization.

His lab's earlier research showed that the extracellular part of the channel looks like four open clamshells, which operate in two pairs. (See illustration right) When four glutamate molecules stick to the inner part of each clam, the shells close halfway. The shell closings pull on the ion channel and force open the channel. During this time, each member of the clam pair is attached to the other member at the external part of their hinges.

In the current paper, Dr. Gouaux found that a few milliseconds after the clamshells pull open the channel, the clams' external hinges pull away from each other, forming a more stable configuration of the receptor that then closes the channel.

Because AMPA receptors help make memories, the new description of AMPA desensitization may aid in the search for drugs that improve memory in Alzheimer's patients. After neurons die in the brain of an Alzheimer's patient, less glutamate—which is normally released by neurons—is around to open AMPA channels. Drugs that may keep channels open longer could compensate for reduced glutamate. Such compounds enhance memory in mice and some are in clinical trials in humans.

Yet increasing the time the AMPA channels remain open is not always desired. In stroke, and Parkinson's, channels stay open for too long and allow excess ions to accumulate in the neurons and kill the cells. Drugs that pull the clams apart faster may reduce neuron death by shortening the time the channels stay open.

Dr. Gouaux also hopes the new picture of AMPA channels will be useful in understanding how the more complex NMDA and kainate glutamate receptors in the brain work. "The AMPA receptor is the Volkswagen of glutamate receptors," Dr. Gouaux says. "We eventually want to understand how a Mercedes receptor like NMDA works, because these receptors may be more important in memory formation and neurodegenerative disease than AMPA."

This work was supported by the Klingenstein Foundation, the National Alliance for Research on Schizophrenia and Depression, and the National Institutes of Health. Dr. Gouaux is an assistant investigator of the Howard Hughes Medical Institute.


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