In a recent email correspondence, Dr. Cunningham at the University of Texas Medical Branch thanked FPWR and described the contribution that FPWR grant funds (2010-2011) have had on the work coming out of her laboratory. She writes, "thank you for the support which allowed us to build an entirely new program to develop therapeutics for those affected by PWS...We have made incredible progress on this research program, thanks in great part for the support from the FPWR.
The goal of Dr. Cunningham’s FWPR funded project "The 5-HT2CR: Mining a new experimental approach to therapeutics for Prader-Willi syndrome" is to develop a novel class of drugs that can influence the serotonin system, specifically the serotonin 2C receptor, which has been reported as having abnormal expression in PWS. Results from this work were recently published in the Journal of Neuroscience and were highlighted by the website Medical News Today.
Serotonin is a neurotransmitter (messenger in the nervous system) that plays a critical role in regulating a wide range of behavior including satiety and mood. Serotonin works by binding to the serotonin receptor on the cell surface which then relays the appropriate message to the cell. Decreased signaling of the serotonin pathway has been linked to both abnormal appetite and depression. Considering the reported disruption in serotonin signaling in PWS, there is great interest in exploring ways to boost this pathway.
Common approaches include increasing the amount of serotonin and/or serotonin receptors. However, Dr. Cunningham’s group is taking an outside the box approach by looking at what other proteins interact with the serotonin receptor and affect its function. This is based on the notion that receptors don’t function in isolation and that complex interactions with other proteins can amplify or dampen their signaling. In the case of the serotonin receptor, once such protein is PTEN.
In more simple terms, imagine wanting to get the maximum brightness (serotonin signaling) in a room (brain or gut). One approach is to add more lamps (serotonin receptors). A second approach is to make sure that all of the lamps are filled with working light bulbs (serotonin). However, a third and complementary approach is to make sure that nothing is blocking the light (signal) by removing anything that might dampen the brightness, for example, a dark or dusty lampshade (PTEN).
In order to disrupt the interaction between the serotonin receptor and PTEN, Dr. Cunningham’s group designed a peptide (small protein fragment) based on the part of the receptor where PTEN interacts. This “tricks” PTEN into binding the peptide fragment instead of the full length functioning serotonin receptor, effectively removing the lamp shade and increasing the strength of the signal.
Moving forward, studies will entail designing more potent peptides with minimal side effects as well as examining the functional effects of these peptides on behavior. We look forward to learning about the continued work as Dr. Cunningham’s group continues to move towards the long-term goals of preclinical (animal) models and a potential therapeutic for serotonin mediated disorders.