An interdisciplinary team of researchers from the University of Texas Medical Branch (UTMB) at Galveston and the University of Houston (UH) has found a new way to influence the vital serotonin signaling system — possibly leading to more effective medications with fewer side effects.
Scientists have linked malfunctions in serotonin signaling to a wide range of health issues, everything from depression and addictions to epilepsy, obesity and eating disorders. Much of their attention has focused on complex proteins called serotonin receptors that are located in the cell membrane. Each receptor has a so-called “active site” specially suited to bond with a serotonin molecule. When that bond is formed, the receptor changes shape, transmitting a signal to the cell’s interior.
Traditional drug discovery efforts target interactions that take place at such active sites, but a receptor’s behavior also can be changed by additional proteins that bind to the receptor at locations that, in molecular terms, are quite distant from the active site. This is done through a process called “allosteric regulation,” which is the mechanism examined by the UTMB-UH team for one specific and highly significant kind of serotonin receptor, designated the 5-HT2C.
“This is a whole new way of thinking about this system, targeting these interactions,” said UTMB professor Kathryn Cunningham, senior author of a paper on the research now online in the Journal of Neuroscience. “Basically, we’ve created a new series of molecules and validated that we can use them to change the way the receptor functions both in vitro and in vivo, through an allosteric effect.”
The UTMB-UH group’s approach centers on the natural interaction between the 5-HT2C receptor, serotonin and another molecule called PTEN. Like serotonin, PTEN controls the 5-HT2C receptor function. Since it does so at a location distant from the active site, it’s possible — and, in fact, common — for a receptor to bind to serotonin and PTEN simultaneously. When this happens, an allosteric effect is produced, such that serotonin signaling is weakened.
“We want to maintain signaling through 5-H2C receptors to gain therapeutic benefits, and to do that we had to reduce the number of receptors that were binding to PTEN molecules,” said UH professor Scott Gilbertson, another senior author on the paper. “One way to do that is to develop an inhibitor that competes with the receptor for binding to PTEN.”
Ultimately, the researchers want to translate this research into therapeutics. The idea of targeting these interactions to produce drug and research tools is new and has notable potential.
“We’ve got the basics down now, so we can use the chemistry to make new molecules that we think might be potentially useful for treatment of addictions, for example,” Cunningham said. “But there’s also an intense interest in figuring out the biology of this interaction between 5-HT2C and PTEN, what it means in terms of disease states like addictions, alcoholism, depression, obesity and eating disorders. I think in a broader sense this is really going to help us understand the neurobiology of these disorders.”
Support for this research was provided by the Klarman Family Foundation, the Foundation for Prader-Willi Research and the National Institute on Drug Abuse.
A copy of the article is available at http://www.jneurosci.org/content/33/4/1615.full.
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