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Rewiring the serotonin system
Date:2/13/2013

neously. When this happens, an allosteric effect is produced: serotonin signaling 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 candidate inhibitor chosen by the researchers was a fragment of the receptor itself specifically, the part of the receptor where PTEN attaches. Such sub-protein structures are known as "peptides"; this one was previously dubbed "3L4F." Test-tube and cell-culture experiments showed that 3L4F boosted 5-HT2C response significantly; that it acted by binding to PTEN; and that it had no effect at all on another type of serotonin receptor, designated 5-HT2A.

Behavioral studies in laboratory rats also 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."

The team took a step toward realizing that potential by trimming 3L4F down to a peptide roughly half its size that retains similar efficacy. Using computational molecular modeling, they determined which elements of this peptide were important to bonding with PTEN information they will use 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
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Contact: Jim Kelly
jpkelly@utmb.edu
409-772-8791
University of Texas Medical Branch at Galveston
Source:Eurekalert

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