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Synaptic Shape Shifters
by Kendall Powell
The atomic structure of this bacterial neurotransmitter transporter (LeuTAa), a homolog of ones found in higher organisms, may illuminate where and how drugs act in humans.
HHMI investigator Eric Gouaux once joked that his lab studies "how the garbage is taken out" of the synapse, the junction between two nerve cells. But it's really no joke: Excess chemicals can lead to chaos in the nervous system.
Gouaux and colleagues published new work on synapses in July 2005, around the same time that two other HHMI laboratories also announced discoveries about how synapses work. The three labs took different approaches, as if viewing the synapse junction through various photographic lenses.
Gouaux's group (then at Columbia University, he has since moved his lab to the Vollum Institute at Oregon Health & Science University in Portland) took a high-resolution close-up of a transporter molecule. Robert B. Darnell's laboratory at the Rockefeller University in New York shot a panoramic view of a whole genome's worth of synapse proteins. And Terrence J. Sejnowski's team at the Salk Institute for Biological Studies in La Jolla, California, modeled synaptic function using a computer simulation. Their collective results may change how researchers define the synapse and its role in the brain cells controlling motor movement, mood, and memory.
First, the close-up. The transporters that move the neurotransmitter serotonin back into nerve cells are a target for antidepression drugs. How those transporters work, though, is still a mystery, which means the drug action also remains unknown. Gouaux's group solved the atomic structure of a bacterial transporter that is structurally similar to the human transporters. Its symmetry and shape suggest which portions of the molecule are involved in binding to the neurotransmitters, which may give clues to where and how drugs will act.
Illustration: Eric Gouaux