PORTLAND, Ore.– Researchers at Oregon Health & Science University's Vollum Institute have uncovered remarkably detailed 3-D views of one of the most important transporters in the brain - the serotonin transporter. Their study, published online today in the journalNature, provides fresh insight into how citalopram and paroxetine, two of the most widely prescribed selective serotonin reuptake inhibitors, or SSRIs, interact with and inhibit serotonin transport.
Visualizing this molecular structure creates a platform for designing new, more effective small molecule therapeutics to treat depression and anxiety.
"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 Eric Gouaux, Ph.D., senior scientist in the Vollum Institute at OHSU, National Academy of Sciences member, and Howard Hughes Medical Institute Investigator. Gouaux is an internationally recognized crystallographer in the area of neurotransmitter receptor and transporter structure.
Influencing virtually all human behaviors, serotonin regulates the activity of the central nervous system as well as processes throughout the body, from cardiovascular function to digestion, body temperature, endocrinology and reproduction. The serotonin transporter acts as a molecular pump for serotonin, recycling the neurotransmitter following neuronal signaling. Serotonin shapes neurological processes including sleep, mood, cognition, pain, hunger and aggression.
When SSRIs were first developed in the 1980s, the molecular identity of the transporter they targeted was unknown. In the 1990s, researchers realized that SSRIs had a common target -- the serotonin transporter. By binding to the transporter and blocking serotonin from being taken back up by the transporter into the cell, SSRIs allow serotonin to remain outside of the cell longer than normal, potentially prolonging neuronal signaling. Though SSRIs are widely used to treat anxiety and depression, the molecular mechanism by which they block the transporter is not fully understood.
Gouaux's lab used X-ray crystallography to capture images of the transporter. In this paper, they report that SSRIs lock the transporter in an outward-open conformation by loading in the central binding site, directly blocking serotonin binding.
The study, "X-ray structures and mechanism of the human serotonin transporter,” was authored by Gouaux; Jonathan A. Coleman, Ph.D.; and Evan M. Green, a research assistant who is now a Ph.D. student at University of California San Francisco.
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.
About OHSU
Oregon Health & Science University is a nationally prominent research university and Oregon's only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children's Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university's social mission. OHSU's Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer's disease and new treatments for Parkinson's disease, multiple sclerosis and stroke. OHSU's Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.
About the OHSU Vollum Institute
The Vollum Institute is a privately endowed research institute at OHSU and is dedicated to basic research that will lead to new treatments for neurological and psychiatric diseases. Vollum scientists have transformed the field of neuroscience and, in particular, have been pioneers in the study of cellular signaling, neuronal development, gene regulation and the neurobiology of disease.
This is all very fascinating, but ignores the fact that the "serotonin hypothesis" as the cause of major depression was disproven as far back as the mid 1980s. There are drugs that increase, decrease, or don't affect serotonin at all which appear to have antidepressant properties. Additionally, increases in serotonin levels occur very quickly after taking SSRIs, while the therapeutic effects usually take weeks to develop. Moreover, Kirsch's work and others' begin to show that for most depressed people, SSRIs provide little to no advantage over a placebo. It is a shame that researchers continue to waste time and energy on an outmoded hypothesis rather than looking at a wider range of causal factors, including studying the very large possibility that not all cases of depression have the same cause or need the same kind of treatment.
Steve McCrea