Two separate studies—published this week in Science and Nature—provide a window into the way tricyclic antidepressants, such as clomipramine and desipramine, provide therapeutic relief by adhering to proteins on the part of a nerve cell's outer membrane that extends into the brain's synapses (spaces between the cells). These so-called transporter proteins, so-named because they carry molecules inside the nerve cell, gobble up neurotransmitters (chemical messengers such as norepinephrine, serotonin and dopamine) sent by neighboring cells. The drainage of these neurotransmitters from synapses—resulting, ironically, from the reimportation of the chemical just secreted by the sending neuron—has been linked to anxiety disorders; tricyclic antidepressants boost the activity of these neurotransmitters in synapses. But scientists have never been sure how this was accomplished.
Both sets of researchers, using a model protein called leucine transporter (from the bacterium Aquifex aeolicus and similar in structure to the human synaptic transporter protein) determined that the drug works by preventing the protein from sucking too many neurotransmitters out of the synapses. But the teams disagree on whether this mechanism also occurs in the human form of the protein, which was too unstable to synthesize.
Using differing microbiological methodology, both teams were able to see exactly how the protein responds to the tricyclic antidepressant molecules. Maarten Reith, a professor of psychology and pharmacology at New York University School of Medicine and co-author of the Science study, says the V-shaped (like the mouth of an alligator) binding site on these proteins catches molecules that are in the synapse. Once it latches onto a molecule that fits, an ion-powered gate locks the captured substance in the protein and later a similar structure on the other end of the protein opens and shoots it into the body of the neuron. "It's kind of like wine tasting," Eric Gouaux, a neuroscientist at Oregon Health and Science University's Vollum Institute in Portland and co-author of the Nature paper, says. "You take sip of wine and you hold it in your mouth. If you think it's good you [may] swallow it, and if it's not good, you spit it out."
The researchers note that the antidepressants do not fit snuggly into the sites that proteins use to trap neurotransmitters; instead, the molecules stick to what Gouaux refers to as a "greasy vestibule" located just above the neurotransmitter binding site. From this contact point the drug can prevent the leucine transport protein from receiving the chemical messenger. Thus, a neurotransmitter like norepinephrine will remain in the synapse, where its increased levels typically alleviate depressionlike symptoms.
"Now people can look at that environment and they know all the [protein's] amino acids (or building blocks) that are not interacting with tricyclic antidepressants," says Reith, whose team also included structural biologist Da-Neng Weng. "A drug that binds more potently might be worthwhile" as a way to relieve symptoms more effectively.
Gouaux isn't quite as optimistic—at least not yet. He sees leucine transporters as reasonable models for the human transporter protein, but does not think the two behave in exactly the same manner. He says that he will continue to glean "general mechanistic features" from leucine transporters and move on to researching the human transporter—a step that could immediately inform new efforts in drug discovery.
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