Cellular and Molecular Studies of Ethanol and Memory

描述（由申请人提供）：谷氨酸受体的NMDA亚型（NMDAR）被认为在发育、突触可塑性、食欲行为和兴奋性毒性中起关键作用。因此，乙醇抑制该受体的能力可能是乙醇在CNS中的SS作用的重要组成部分。然而，对于乙醇影响NMDAR的分子机制只有有限的了解。在重组系统和培养的胎儿神经元中的研究表明，乙醇可以产生非常快速的作用（~50 msec），这可能部分是由于乙醇与受体胞外结构域中的结合口袋相互作用。对脑切片的研究表明，乙醇对突触NMDAR的影响可能需要10-15分钟才能达到最大水平，并且影响的程度随着发育和脑区域的变化而变化很大，并且可以通过多巴胺等递质进行调节。这些数据表明，乙醇对NMDAR的作用可能有多种机制。包括PI在内的许多不同小组最近的研究表明，磷酸化可能在乙醇对NMDAR的影响中起作用。然而，尚不清楚乙醇是否通过减少其磷酸化来抑制NMDAR，或者磷酸化是否影响受体的乙醇敏感性，或者两者兼而有之。目前的建议的目标是研究磷酸化在乙醇对NMDAR的影响中的作用。该提案将侧重于对三个具体假设的检验。1.验证磷酸化在乙醇抑制NMDAR 2中起重要作用的假设。检验乙醇通过激活磷酸酶影响NMDAR的假设。和3.检验乙醇通过影响受体的表面表达来影响NMDAR功能的假设。希望这些研究能加深我们对乙醇对NMDAR影响的理解，从而有助于更好地理解乙醇对认知功能的影响

DESCRIPTION (provided by applicant): 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