In the nervous system, serotonin is a widely disseminated, well-studied intercellular messenger. It exerts a spectrum of both subtle and overt effects ranging from the control of appetite to the modulation of mood swings. The diversity of messages that are delivered by 5-HT arise from its interaction with one or more of the 14 pharmacologically distinct receptors that are expressed on the appropriate cells. Serotonin's role as a neurotransmitter tends to overshadow the fact that it (or serotonin-like) molecules existed in plants before the evolutionary emergence of mammals. In fact, only 5% of the body’s supply of serotonin is found in the central nervous system, the vast majority is located in the gut. Moreover, serotonin and its cognate receptors mediate developmental regulatory pathways in Drosophila and other insects. Moreover, serotonin has well characterized regulatory effects on proliferation, migration and maturation in a variety of mammalian cell types, including lung, kidney, endothelial cells, mast cell, and astrocytes.
Our laboratory has spent the last several years showing that serotonin-mediated pathways are embedded in white blood cells and are essential for mounting immune responses. Our research in this area has grown to cover a diverse array of studies (see below).
One of the major areas of research concerns defining the role of serotonin in the growth of cells. In the process of looking for negative controls, we attempted to find human cells (or other higher eukaryotic cells) that did not respond to serotonin or have the ability to self-synthesize this molecule. We were unable to identify any cells that did not respond to serotonin. Serotonin is normally contained within the media used to culture cell lines. When all of the serotonin is removed from the media, within 24 hours the cells will synthesize their own serotonin and secrete it into the media. Consequently, we believe that serotonin may be an autocrine growth factor that is essential for cellular proliferation. In other words, the cells make their own serotonin that is ultimately used to provide growth signals for the cell cycle. We are currently testing this hypothesis using RNAi silencing techniques.
Another major area of research concerns the role of serotonin in determining the development of humoral and cytotoxic immunity. We know that serotonin is passed from an antigen presenting cell to a naïve T cell in the process of activation. These signals stimulate the cell cycle and lead to proliferation. We are currently testing the hypothesis that, in addition to its mitogenic activity, serotonin aids in the signals that lead to differentiation of the activated T cells and aid in the determination of the type of immune response that develops in response to a given antigen.
Serotonin pathways found in the CNS and immune system may have had a common evolutionary origin and then diverged to acquire specialized functions. Accordingly, we have observed similarities in the receptors between the nervous and immune systems as well as striking differences. We have found an unusually spliced mRNA transcript that may encode a new type of serotonin receptor. We have cloned this transcript and are in the process of characterizing the expressed product.
Prior to our entry in to the serotonin studies, the laboratory was involved in structure-based drug design studies. Although, the research is mostly focused on the serotonin projects, we still collaborate with other laboratories in drug design efforts.