Glutamate receptors mediate the majority of excitatory synaptic transmission in the central nervous system, and are involved in many normal brain functions, including neuronal development, cell migration, and plasticity at excitatory synapses. In addition, over-activation of glutamate receptors has been hypothesized to contribute to seizure generation, ischemia-induced cell death associated with head trauma and stroke, and neurodegenerative disorders ranging from Alzheimer's to Parkinson's disease. The central role of these receptors in normal brain function as well as their potential role in these costly and devastating neurological disorders creates an unusually strong rationale for understanding how these receptors are regulated at all levels, from control of transcription to modulation of postsynaptic function. The goal of the experiments outlined in this proposal is to explore the efficiency of coupling between agonist binding and receptor activation (i.e. efficacy) for all three classes of glutamate receptors. Experiments are designed to explore the mechanism underlying regulation of glutamate receptor function by kinases and phosphatases such as calcineurin and PKA, which are colocalized. The link between subunit composition and agonist efficacy also will be explored. These experiments focus on recombinant receptors, because receptor heterogeneity in neurons both cultured and in situ might confound interpretation of the data. Experiments are designed to specifically address the following questions: 1. Do PKA and calcineurin have reciprocal effects on glutamate-efficacy at non-NMDA receptors? 2. Does subunit composition control glutamate efficacy at glutamate receptors? 3. Do tyrosine kinases alter coupling efficiency between glutamate binding and NMDA channel opening? The results of the proposed experiments hold broad implications for the roles of glutamate receptors in normal and pathological conditions. For example, the experiments with non-NMDA receptors may provide a critical test of current models describing mechanisms of postsynaptic LTP. In addition, changes in receptor efficiency introduce an additional source of noise into signal neuronal networks, which holds implications for information processing and stochastic resonance. The work on NMDA receptors will help to define both how receptors function at their most basic level, and provide insight into how their function is regulated by tyrosine kinases, which can be activated by a host of neurotransmitters and hormones. Finally, the possibility that cells could place in error highly efficient receptors at synapses holds interesting implications for epilepsy and neurodegenerative diseases. Thus, the proposed studies will provide foundational information that addresses gaps in current understanding of glutamate receptor function at a variety of levels.
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