Neuroscience, Structural Biology
Oregon Health & Science University
Dr. Gouaux is also a senior scientist at the Vollum Institute of Oregon Health & Science University.
Molecular Mechanisms of Receptors and Transporters
As a middle schooler, Eric Gouaux joined his classmates in taking a career aptitude test to help decide what careers might suit them. While some students were advised to consider law and medicine, Gouaux's results told him to become a cartographer—a mapmaker.
After obtaining undergraduate and graduate degrees in chemistry from Harvard, Gouaux, who specializes in crystallography and visualization of molecules, finds that aptitude test may not have been so far off.
"I make maps of molecules," Gouaux laughs. "Cartography is precisely what I do."
As a molecular mapmaker, Gouaux found himself drawn to the complexity of the problems of the nervous system and the brain. "The nervous system is such a huge frontier," he says. "And, our knowledge of how the brain works is still crude. It's a very tough problem." Gouaux has focused on proteins involved in the elaborate game of "ring and run" that nerve cells play with each other. "In order to control movement, memory, and learning, neurons need to press each others' doorbells and get out of there fast," Gouaux says, referencing the childhood game that kids play—much to the annoyance of their neighbors. "I want to know how a signal activates a neuron and then how that signal is extinguished. I'm really fascinated by how nature accomplishes this on the millisecond timescale."
Nerve cells—called neurons—communicate by rapidly converting electrical signals into chemical signals and then converting them back into electrical signals. To propagate an electrical impulse, neurons in the brain launch bursts of various neurotransmitter molecules at the junction between neurons, called the synapse. Receptors lodged in the membranes of neurons on the receiving end of that burst respond by fielding the neurotransmitters and opening ion channels. In Gouaux's vernacular, this is the "ring." His lab is studying how the atomic structure of a particular neurotransmitter receptor, the glutamate receptor, is related to its function as an ion channel when triggered by the neurotransmitter glutamate.
"One of the things we know is that once glutamate diffuses from one neuron to the next, it 'rings' the bell and causes the ion channel to open," Gouaux says. "Then it closes in a fraction of a second and enters a period of desensitization. We've had no [molecular explanation] for desensitization, even though scientists could measure it electrically since the 1940s."
Gouaux's lab has been working on putting together a picture of what happens during desensitization. Using x-ray crystallography and biophysical and electrical measurements, they have made inroads into understanding the process. The glutamate receptor exists in the cell membrane as four subunits. Gouaux's group found that, as glutamate binds, each subunit undergoes a structural change that opens the ion channel. Immediately after the ion channel opens, the four subunits rearrange themselves, closing the channel and entering the desensitized state.
"It's great that we have information about this receptor," Gouaux says. "But our understanding of the glutamate receptor comes from taking it apart. I want to try understand how these [multiple subunit] membrane receptors work in their natural state. The days of the ultrareductionist approach—of taking a system apart and looking at one component—are over for us."
Although chasing the "ring" has changed Gouaux's approach to science, his biggest scientific surprise came as he explored the "run" side of the synaptic game. Once a neuron fires a burst of neurotransmitters such as glutamate, the neurotransmitter is quickly mopped up from the synaptic space, or cleft, by transporter proteins.
"We scientists didn't have the vaguest idea about how the cell manages to vacuum out the synaptic cleft," says Gouaux. However, understanding the process is extremely important because some of the most important drugs for depression—such as Prozac, Celexa, and Zoloft—target these transporter proteins. "Because we don't understand the transporter proteins, the underlying mechanism for [many depression drugs] remains a mystery."
To obtain a better understanding of how a glutamate transporter protein removes glutamate from the synaptic cleft, Gouaux and his colleagues focused on a bacterial glutamate transporter and used x-ray crystallography, an analytical technique that deduces structure.
"When we got a look at the structure of this protein, it was totally different from any other transmembrane protein we'd seen," Gouaux says. "It looks like this crazy bowl stuck deep inside the membrane. The bottom of the basin is halfway across the membrane."
Forming pockets in the membranes of nerve cells, the transporter protein binds glutamate at the bottom of the bowl and moves it into the cell, quenching the glutamate signal. "The transporter's structure is fascinating," Gouaux says. "But, we still don't know how the glutamate gets from the bottom of the bowl to the inside of the cell."
While deducing the mechanism of the glutamate transporter's action could lead to important new drug therapies to treat disorders ranging from depression to schizophrenia, Gouaux is happy to let others focus on drug development. "Hopefully, our understanding of these processes will help someone create a beneficial drug," Gouaux says. "My interest is to understand the basic mechanisms."
As the field matures, Gouaux expects there will be many more intriguing discoveries. "We are really at a point where we need to look at how these molecules work in their natural environment, which is much more complicated and will require sophisticated visualization and computational approaches," Gouaux says. "I think there will be so many more surprises."