Glutamate Gated Channels in Central & Peripheral Neurons

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DESCRIPTION (provided by applicant): The long-term objective of my work is to provide a better understanding of synaptic transmission by studying the operation of NMDA, AMPA, and kainate receptors, which form ion channels gated by the neurotransmitter glutamate. Another major goal is to uncover properties of these receptors that may allow for clinical intervention to prevent excitotoxic cell death or to provide analgesia. The experiments outlined in this application focus on the regulation of kainate receptor composition and on the regulation of AMPA receptor sub-cellular distribution. In a series of studies on the electrophysiology of kainate receptors in neurons from the hippocampus, spinal cord and dorsal root ganglia, we have shown that each of these cell populations express kainate receptors with distinct pharmacological properties. The experiments in Specific Aim 1 will use molecular biology, physiology and subunit deficient mice to investigate the structural basis for these differences. Specific Aim 2 is focused on the role of specific kainate receptor subunits in spinal synaptic transmission. We have recently demonstrated three different ways in which kainate receptors participate in synaptic transmission in the dorsal horn of the spinal cord. Experiments in this aim will seek to determine whether the G1uR5 or GIuR6 subunits are required for the postsynaptic kainate receptors that mediate a component of primary afferent transmission, or for the presynaptic kainate receptors that modulate transmitter release from primary afferents and from spinal interneurons. The third major Aim of this application is to investigate the control of glutamate receptor distribution on hippocampal neurons by the low molecular weight GTPase rab 5 and other components of the endocytic trafficking pathway.