Researchers at OHSU’s Vollum Institute have revealed the molecular structure of the serotonin transporter (SERT), providing new insight into the mechanism of antidepressant action of two widely prescribed selective serotonin reuptake inhibitors (SSRIs) commonly used to treat depression. In their paper, “X-ray structures and mechanism of the human serotonin transporter,” published Apr. 6, in the journal Nature, authors Jonathan Coleman, Ph.D., Eric Gouaux, Ph.D., and Evan Green, describe their use of X-ray crystallography to capture images of human SERT structures. They report how the antidepressants citalopram and paroxetine lock SERT in an outward-open conformation, directly blocking serotonin binding. Visualizing this structure provides a blueprint for future drug design to treat anxiety and depression.
Serotonin is a key neurotransmitter that regulates various processes throughout the body including sleep, appetite, memory, learning, and mood. Serotonin deficit has long been associated with anxiety and depression. SSRIs act on the SERT by blocking the reuptake process, allowing serotonin to remain outside the cell longer. Increasing levels of available serotonin has been shown to improve feelings of well-being and happiness, but, until now, the molecular mechanism by which SSRIs block the transporter was not fully understood.
“The heavy toll that devastating illnesses like anxiety and depression have on families and communities is, in many ways, incalculable. Revealing the precise structure of the serotonin transporter holds tremendous promise for the development of life-changing drug treatments for these diseases,” said Gouaux.
Gouaux is an internationally recognized crystallographer in the area of neurotransmitter receptor and transporter structure. A National Academy of Sciences member and Howard Hughes Medical Institute Investigator, Gouaux was recently named the Jennifer and Bernard Lacroute Term Chair in Neuroscience Research. The Lacroutes are sponsoring this term chair, “with the enthusiasm and hope that Dr. Eric Gouaux’s work will unravel the work of the neuron for scientists throughout the world.” The term runs through December 2019.
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This work was supported by Bernie and Jennifer LaCroute and the National Institutes of Health (NIH) (5R37MH070039). Coleman has support from a Banting postdoctoral fellowship from the Canadian Institutes of Health Research.