Dr. Stephen F. Traynelis Rollins Research Center, 1510 Clifton Road My laboratory studies the basic principles underlying the structure, function and regulation of the ligand gated ion channels involved in excitatory synaptic transmission. Our focus is on all classes of glutamate receptor, the main excitatory neurotransmitter receptor in the central nervous system. We combine electrophysiological, single channel, structural approaches in an effort to better understand how glutamate receptors work. The primary goal of this work is to use the information about the structure and function of this receptor class to understand normal brain functions that involve synaptic transmission, such as learning and memory. In addition, information about regulation of the ion channels involved in excitatory synaptic transmission can provide insight into the neuropathology of epilepsy, stroke, as well as the response of the central nervous system to brain injury. We are attempting to translate information about the regulation of glutamate receptor function into novel therapeutic strategies. This involves the identification of novel compounds, in collaboration with colleagues in the Department of Chemistry, with novel mechansims of action that can serve as a first step to design new therapeutic agents. My laboratory also examines the role of blood proteases in brain function and injury. We are currently studying the roles of protease activated receptor-1 and protease activated receptor-2 (PAR1 and PAR2) in astrocytic-neuronal crosstalk as well as in neuronal injury and gliosis following brain insult. Published data show a role for PAR1 in mediating harmful events following transient focal ischemia and hypoxia-ischemia in vivo. Our working hypothesis is that activation of PAR1, which is predominantly expressed in astrocytes in both rodent and human, potentiates NMDA receptor function secondary to depolarization-mediated relief of voltage dependent Mg2+ blockade. The increase in NMDA receptor function ultimately leads to elevated intracellular Ca2+ and cell death. The mechanism of PAR1-mediated potentiation of NMDA receptors appears to depend on elevation of glial intracelular Ca2+, and release of glutamate from astrocytes onto neurons to induce depolarization. This mechanism could also serve as a means to regulate synaptic strength under normal conditions, and likely transfers to other G protein-coupled receptors. Finally, we are studying the role of PAR2 in microglial activation. Microglia are the macrophages of the CNS, and respond to injury through a complex process of activation, involving shape changes, proliferation, release of chemokines and cytokines, and increased phagocytosis. The role of microglial activation in brain injury is complex, and an intense area of research. Both harmful and helpful effects of microglial activation have been described. Our experiments involve assessing the effects of PAR2 activation in microglial responses to injury. Such activation could be mediated by, for example, mast cell degranulation and release of tryptase. This work is ultimately directed towards identifying new therapeutic strategies to treat brain injury, as well as build our foundational knowledge about the role of serine proteases in brain function.
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