Receptor Tyrosine Kinase Transactivation in Neuronal Signalling, Stress, and Survival

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Brain cells (neurons) communicate with one another using protein "receptors". Major types of protein receptors include G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and ion channels such as the N-methyl-D-aspartate (NMDA) receptor. How the signalling of one type of receptor is influenced by the others (receptor cross-talk) is less understood. Our lab works to better understand a specific type of cross-talk called "RTK transactivation", how it influences neuronal activity, its role in responding to neuronal stress, and promoting neuronal survival. This research is needed so we can fully understand the complexity of brain function in both healthy neurons, damaged neurons, or neurons experiencing stress. Much of the work describing RTK transactivation research has been descriptive and carried out in non-neuronal models. One of our research objectives is to characterize RTK transactivation pathways in both neurons (primary cultures and ex vivo brain slice) and in novel neuronal-like cell lines such as the hippocampus-derived Ht22 cell line. In addition to answering several fundamental questions about RTK transactivation, developing these new model systems will be valuable to other researchers in neuroscience, including those interested in employing the Ht22 cell line as a hippocampal-like model. Beyond the basic characterization of RTK transactivation, our second objective is to study the consequences of RTK transactivation on neuronal signalling, activity, and survival with a focus on NMDA receptor signalling and excitotoxicity (when NMDA receptors are over-activated). We have demonstrated that the 5-HT7 receptor is able to regulate NMDA receptor signalling and reduce excitotoxicity via platelet-derived growth factor (PDGF) receptor and TrkB receptor transactivation. In several cells and tissues, including cardiac myocytes, vascular smooth muscle cells, pulmonary and renal epithelial cells, and in white blood cells, RTK signalling, and RTK transactivation specifically, is altered by stress or tissue damage. Our third objective is to determine the role of RTK transactivation in the neuronal response to stress. Does neuronal stress initiate RTK transactivation pathways as observed in other cell types? Are specific GPCR-RTK transactivation pathways disrupted in neuronal stress? Determining the scope of changes in RTK signalling and transactivation in neuronal stress will provide a more robust understanding of the cellular responses to stress in neurons. As our research involves multiple techniques, model systems, and collaborations with other researchers, students in my lab will gain a diverse set of skills that will allow them to continue to advance knowledge in academic and industrial settings. The outcomes of our research will impact scientists and researchers across several disciplines, including basic and applied neuroscience, stress and stress neurobiology, as well as researchers in neuropsychiatry and neurology.