The NMDA subtype of glutamate receptor (NMDAR) is thought to play critical roles in development, synaptic plasticity, appetitive behaviors and excitotoxicity. Therefore ethanol's ability to inhibit this receptor is likely to be an important component of ethanol'ss action in the CNS. However, there is only a limited understanding of the molecular mechanism(s) by which ethanol affects the NMDAR. Studies in recombinant systems and in cultured fetal neurons have shown that ethanol can produce very rapid effects (~50 msec) that may be due, in part, to ethanol interacting with a binding pocket in the extracellular domain of the receptor. Studies in brain slices show that ethanol effects on synaptic NMDAR can take 10-15 minutes to reach maximal levels and that the magnitude of the effect varies widely with development and brain region and can be modulated by transmitters such as dopamine. Such data suggest that there may be multiple mechanisms of ethanol action on the NMDAR. Recent studies by a number of different groups including the Pl's have suggested that phosphorylation may play a role in ethanol's effects on the NMDAR. However it is not known whether ethanol inhibits the NMDAR by reducing its phosphorylation or whether phosphorylation affects the ethanol sensitivity of the receptor or both. The goal of the current proposal is to investigate the role of phosphorylation in ethanol's effects on the NMDAR. The proposal will be focused on tests of three specific hypotheses. 1. Test the hypothesis that phosphorylation plays an important role in ethanol's inhibition of the NMDAR 2. Test the hypothesis that ethanol affects the NMDAR by activating a phosphatase. And 3. Test the hypothesis that ethanol influences NMDAR function by affecting the surface expression of the receptor. It is hoped that theses studies will enhance our understanding of ethanol's effects on the NMDAR contribute thereby to a better understanding of the effects of ethanol on cognitive function ? ?
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