From The Quarterly, Summer 2013
Bryan L. Roth, M.D., Ph.D., Foundation Scientific Council Member, received a NARSAD Young Investigator Grant in 1992 to study the structure and function of serotonin receptors. At the time, he was having difficulty securing funding for his idea that understanding these receptors would be crucial for the development of safer and more effective psychiatric medications. Serotonin receptors are molecules on nerve cells that bind to the neurotransmitter serotonin and are the targets for many medications prescribed for a variety of ailments, including, importantly, depression and schizophrenia.
This year, Dr. Roth, in an international collaboration with colleagues at The Scripps Research Institute in California and the Chinese Academy of Sciences, identified the structures of two of 14 known serotonin receptors (the two are known as 5-HT1B and 5-HT2B). The research team used X-ray crystallography, a technology in which X-ray beams are fired at crystals of the compound in question to deduce the atomic structure from the scatter pattern of the beams. The researchers also investigated how differences in binding affected chemical signaling in the serotonin pathway. The results of their work were published in back-to-back papers in the May 3rd issue of the journal Science.
The two receptors were found to have very similar structures in the areas where serotonin docks, but in one area of the 5-HT1B receptor, the binding pocket was wider, a tiny difference but enough to explain why the two receptors bind differently to certain compounds. The distinction may be relevant to the safety of medications: some medications that activate 5-HT2B are thought to cause heart problems and have been withdrawn from the market.
“Nearly all psychiatric drugs including virtually all drugs which treat schizophrenia affect serotonin receptors to some extent. These receptors also mediate a host of effects outside the brain, for example, on blood coagulation, smooth muscle contraction and heart valve growth,” explained Dr. Roth.
“These new findings will facilitate the development of more precise medications that avoid potentially harmful “off-target” effects with greater beneficial actions.”
An editorial accompanying the Science papers explains the importance of the work: “Experimental methods developed by Bryan Roth enable neuroscientists to follow the pathways taken by messages sent between neurons in complex networks in the brain here used to identify structure and function of serotonin receptors. The work offers a valuable framework for designing safer and more effective medications.”
An international team of scientists is working to decode the actions in the brain of widely used medications for depression and schizophrenia, knowledge that can be used to design more precise treatments.
Bryan L. Roth, M.D., Ph.D.
Chair Protein Therapeutics and Translational
Proteomics; Director, National Institute of Mental Health Psycho-active Drug Screening Program, University of North Carolina School of Medicine;
1992, 1998 and 2008 NARSAD Young, Independent and Distinguished Investigator Grantee
Foundation Scientific Council Member