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Researchers discover how antidepressants and cocaine interact with their protein targets in brain cells

Scientists from Weill Cornell Medical College (WCMC) and Columbia University Medical Center have described for the first time the specifics of how brain cells process antidepressant drugs, cocaine and amphetamines. The findings could lead to the development of more targeted medications for a host of psychiatric diseases, particularly depression and drug addiction.

The research, featured as the cover story in a recent issue of Molecular Cell, describes the precise molecular and biochemical structure of transporter molecules known as neurotransmitter-sodium symporters (NSSs), and how cells use them to enable neural signaling in the brain. A second study, published in a recent issue of Nature Neuroscience, pinpoints the sites on NSSs where cocaine binds.

"These findings are so clear and detailed at the level of molecular behavior that they will be most valuable to developing more effective therapies for mood disorders and neurologic and psychiatric diseases, and to direct effective treatments for drug addiction to cocaine and amphetamines," said co-lead author Harel Weinstein, the Maxwell M. Upson Professor of Physiology and Biophysics and director of the Institute for Computational Biomedicine at WCMC. "This research may also open the door to the development of new therapies for dopamine-neurotransmitter disorders, such as Parkinson's disease, schizophrenia and anxiety and depression."

In the Molecular Cell study, a research team led by Jonathan Javitch, professor of psychiatry and pharmacology in the Center for Molecular Recognition at Columbia University Medical Center, used the crystal structure of a bacterial transporter that is very similar to human neurotransmitter transporters to design laboratory experiments that were combined with the computer simulations in the Weinstein lab.

The team stabilized different structural states of the NSS molecule that relate to steps in its function; they found a finely tuned process in which two sodium ions bind and stabilize the transporter molecule for the correct positioning of two messenger molecules -- one deep in the center of the protein and the other closer to the entrance. Like a key turning to engage a lock mechanism, this second binding causes changes in the transporter throughout the structure, allowing one of the two sodium molecules to move inward and then release the deeply bound messenger and its sodium partner into the cell.

In the bacterial transporter studied, antidepressant molecules bind in the outer one of two sites and stop the transport mechanism, leaving the messenger molecule outside the cell.

The second team of researchers, involving a collaboration of the Weinstein and Javitch labs with colleagues in Denmark, found that in the human dopamine transporter cocaine binds in the deep site, unlike the antidepressant binding in the bacterial transporter. Therefore, the researchers conclude that anti-cocaine therapy will be more complicated than was previously expected, because interfering with cocaine binding also means interference with the binding of natural messengers.

"This finding might steer anti-cocaine therapy in a completely new direction," Weinstein said.

Molecular understanding at this level of structural and dynamic detail is rare in the world of drug development, the authors note. Only about 15 percent of all drugs have a known molecular method of action, even though the effects of these drugs within the body are well understood pharmacologically.

The research was supported by the National Institutes of Health, with additional funding from the Danish Medical Research Council, the Lundbeck Foundation, the Novo Nordisk Foundation and the Maersk Foundation.

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