February 15, 2013
A Rewired Serotonin System May Help Medications Be More Effective With Fewer Side Effects
Lee Rannals for redOrbit.com — Your Universe Online
One new method may be able to lead to more effective medications, with fewer side effects, according to research published in the Journal of Neuroscience.Scientists from the University of Texas Medical Branch (UTMB) at Galveston and the University of Houston found a new way to influence the vital serotonin signaling system. The team linked malfunctions in serotonin signaling to a range of health issues, including everything from depression and addictions, to epilepsy and obesity.
Much of the attention focused on complex proteins known as serotonin receptors, which are found in the cell membrane. Each of these receptors have "active sites" suited to bond with a serotonin molecule.
Traditional drug discovery efforts target interactions that take place at these sites, but a receptor's behavior can be changed by additional proteins that bind to it at locations farther from the active site. This process is known as "allosteric regulation."
"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. "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 group focused on the natural interaction between the 5-HT2C receptor, serotonin, and a molecule called PTEN, which controls 5-HT2C receptor function. They said that it is possible for a receptor to bind to serotonin, and PTEN simultaneously, which causes an allosteric effect where serotonin is weakened.
"We want to maintain signaling through 5-HT2C 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."
The researchers chose a fragment of the part of the receptor where PTEN attached. These sub-protein structures are known as "peptides." The team also looked at behavioral studies in laboratory rats, which indicated that 3L4F increased 5-HT2C responses.
"We looked at both human cells and rats because ultimately we want to translate this research into therapeutics," said UTMB postdoctoral fellow Noelle Anastasio, lead author of the paper. "The idea of targeting these interactions to produce drug and research tools is truly new and has great potential."
With this study, the team determined that elements of peptides were important to bonding with PTEN. This information can be used to design smaller molecules with the same or better activity.
"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 the addictions, alcoholism, depression and obesity and eating disorders. I think in a broader sense this is really going to help us understand the neurobiology of these disorders."
Recently, researchers published another study in the Journal of Neuroscience about how tracking a single protein that regulates serotonin makes it possible to study the dynamics of the protein that regulates mood, appetite and sleep. The team in this research had to tag these proteins in order to follow their motion on the surface of cells in real time.
“By understanding the basic mechanisms that naturally turn serotonin transporter activity up and down, maybe we can develop medications that produce milder side-effects and have even greater efficacy,” said Randy Blakely, the Allan D. Bass Professor of Pharmacology and Psychiatry. “Our sights are also focused on transferring what we have learned with normal serotonin transporters to an understanding of the hyperactive transporters we have found in kids with autism.”