Scientists from a UH and University of Texas Medical Branch interdisciplinary research group have found a new way to impact the serotonin signaling system that could lead to more effective medications with fewer side effects.
“We do a significant amount of work in collaboration with biomedical researchers in the Houston/Galveston area,” said UH chemistry professor Scott Gilbertson. “Many of our projects provide us with a unique opportunity to test biological activity of our compounds and make modifications in biological principles.”
The research team is looking into failures in the serotonin signaling system that can be connected to serious health issues like depression, addiction, obesity, epilepsy and eating disorders.
A main focus is on the complex proteins called serotonin receptors in the cell membrane. Serotonin receptors — also known as 5-HT receptors — influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep and thermoregulation.
“Our goal is to maintain signaling through 5-HT2C receptors, which is a subtype of 5-HT receptor, to achieve therapeutic benefits, and to reduce the number of receptors binding to PTEN molecules,” Gilbertson said. “To achieve that, we want to develop a competing inhibitor with the binding receptors to PTEN.”
According to the interdisciplinary research, the candidate inhibitor chosen is a fragment of the receptor itself, more specifically, the part of the receptor where PTEN is attached.
These “sub-protein structures” are known as peptides, and this one was previously titled 3L4F. Experiments have shown that 3L4F heightened 5-HT2C responses considerably.
“Ultimately we want to translate this research into therapeutics,” said UTMB postdoctoral fellow Noelle Anastasio. “The idea of targeting these interactions to produce drug and research tools is truly new and has great potential.”
UTMB professor Kathryn Cunningham said serotonin signaling through the 5-HT2C receptors is critical in normal psychology, whereas abnormal 5-HT2C functions are thought to contribute to the pathogenesis of multiple neural disorders.
The serotonin interacts with specific protein partners; however, the impact of the interactions on 5-HT2C functions is inadequately understood.
“The compelling data demonstrates the specificity and importance of this protein assembly in cellular events and behaviors in serotonin signaling,” said Cunningham. “It also provides a chemical guidepost to the future development of drug-like peptides or small-molecule inhibitors to study allosteric and therapeutics for 5-HT2C-mediated disorders.”
The research team took a crucial step toward realizing that potential by trimming down the 3L4F peptide to roughly half its size, while retaining similar efficacy. Using computational molecular modeling, they determined which elements of this peptide were important to bond with PTEN. This information will be used to design smaller molecules with the potential to achieve 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 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.”