New York, NY (August 8, 2018)–Researchers at Columbia University Irving Medical Center (CUIMC) have found new evidence of how certain transport proteins are working at the molecular level, paving the way for new, improved drugs to treat psychiatric disorders.
The study's findings have been published in the prestigious Proceedings of the National Academy of Sciences of the United States (PNAS).
Neurotransmitter:sodium symporters (NSS) regulate signals between nerve cells, and are the molecular target of antidepressants (SSRIs like Prozac) and of various psychostimulants. The understanding of their structure and function, therefore, is key to the development of appropriate therapeutics to treat disorders such as depression, anxiety, and obsessive-compulsive disorder (OCD), which are a burden to millions of people in the US.
Led by CUIMC researchers Matthias Quick, PhD, Associate Professor of Neurobiology (in Psychiatry) at Columbia University Vagelos College of Physicians and Surgeons and Jonathan Javitch, MD, PhD, Lieber Professor of Experimental Therapeutics in Psychiatry and Professor of Pharmacology at Columbia University Vagelos College of Physicians and Surgeons, the team had previously studied a bacterial version of NSS (LeuT). This work revealed the existence of an unexpected second substrate binding site that was shown to also bind drugs. The team's new study examined another bacterial NSS homolog (MhsT) that is even more functionally similar to its human counterparts. Their finding of a second substrate binding site in this NSS, too, powerfully suggests that the same configuration is likely found in human NSS as well, and dispels much of the previous skepticism.
"These data suggest that the involvement of two binding sites in neurotransmitter transport is not unique to LeuT but shared by other NSS members, and is possibly a universal feature of these many transport proteins," says Dr. Javitch.
The study of neurotransmitter:sodium symporters has proven challenging, and three-dimensional images of LeuT were first captured only in 2005 using X-ray crystallography. While a central binding site was identified in the crystal structure, imaging of the second binding site remains elusive, and its identification has required biochemical, biophysical and computational approaches.
"Looking forward, incorporating the knowledge from this new discovery into future NSS research could lead to better-informed therapeutics research and design, ultimately improving the lives of the millions of Americans afflicted with psychiatric disorders," says Dr. Quick.
The study is titled "The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites."
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The other authors of this paper are Ara M. Abramyan, PhD (NIH/NIDA/IRP), Pattama Wiriyasermkul, PhD (CUIMC), Harel Weinstein, DSc (Weill Cornell Medical Center), and Lei Shi, PhD (NIH/NIDA/IRP).
The study was supported by grants from the National Institutes of Health (U54 GM087519, R01 DA041510, and P01 DA012408), and by the Intramural Research Program of National Institutes of Health, National Institute on Drug Abuse.
The authors report no financial or other conflicts of interest.
Columbia University Department of Psychiatry
Columbia Psychiatry is among the top ranked psychiatry departments in the nation and has contributed greatly to the understanding and treatment of brain disorders. Co-located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Irving Medical Center campus in Washington Heights, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at the Columbia University Vagelos College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, eating disorders, substance use disorders, and childhood psychiatric disorders.
Columbia University Irving Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Irving Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.
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http://dx.doi.org/10.1073/pnas.1717444115
