REGULATION OF SIGNALING BY MGLUR5

描述（改编自申请人摘要）： 海马体是边缘皮质结构，其在以下方面起重要作用： 学习和记忆，是颞叶癫痫的主要部位， 老年痴呆症谷氨酸是兴奋性神经递质的主要来源。 突触在海马体，在那里它的作用都离子和代谢 谷氨酸受体（mGluRs）。特别关注的是《国家地雷行动计划》， 谷氨酸受体亚型，因为它在某些形式的 学习、记忆和病理状况，包括癫痫反应， 兴奋性毒性有趣的是，最近的研究表明， mGluR亚型mGluR5可显著增强通过NMDA的电流 海马神经元中的受体通道。此外，低浓度 NMDA增强对mGluR5活化的响应。这种积极的反馈 mGluR5和NMDA受体之间的调节可能在 信号放大，并可能是重要的NMDA受体功能。 与此相一致的是，之前的几项研究表明mGluR5在体内起着重要的作用。 在突触可塑性的几种受体依赖形式中起重要作用， 可能导致NMDA受体激活的病理反应。 先前的研究表明mGluR5通过激活蛋白质而脱敏， 激酶C（PKC），其直接磷酸化受体。 我们最近发现，轻度激活的NMDA受体-与低 浓度的NMDA-通过逆转这一点来增强mGluR5介导的反应。 激动剂诱导的脱敏有趣的是， 受体减少mGluR5介导的反应，增加mGluR5 磷酸化鉴于最近的研究，这一点特别有趣， 表明低频刺激海马神经传入 海马CA1区诱导蛋白磷酸酶的优先激活 而高频刺激导致PKC的激活， 蛋白质磷酸化的净增加。基于这一点和其他一些 以前的研究，我们假设，不同的影响， mGluR5上的NMDA浓度是由以下物质的净增加和减少介导的： mGluR5磷酸化。此外，我们假设低频 刺激多巴胺能传入神经诱导优先去磷酸化 的mGluR5和增强mGluR5介导的反应，而高频率 刺激诱导mGluR5磷酸化的净增加， mGluR5介导的反应。分子生物化学和 电生理学技术将用于直接测试这些假设。

DESCRIPTION(Adapted from applicant's abstract): The hippocampus is a limbic cortical structure that plays an important role in learning and memory, and is a primary site of temporal lobe epilepsy and Alzheimer's disease. Glutamate is the primary neurotransmitter at excitatory synapses in the hippocampus, where it acts on both ionotropic and metabotropic glutamate receptors (mGluRs). Particular attention has been focused on the NMDA subtype of glutamate receptor because of its unique role in certain forms of learning, memory, and pathological conditions including epileptic responses and excitotoxicity. Interestingly, recent studies reveal that activation of one mGluR subtype, mGluR5, can dramatically potentiate currents through NMDA receptor channels in hippocampal neurons. Furthermore, low concentrations of NMDA potentiate responses to mGluR5 activation. This positive feedback regulation between mGluR5 and NMDA receptors could play a critical role in signal amplification and may be important for NMDA receptor function. Consistent with this, several previous studies suggest that mGluR5 plays an important role in several receptor-dependent forms of synaptic plasticity and could contribute to pathological responses to NMDA receptor activation. Previous studies reveal that mGluR5 is desensitized by activation of protein kinase C (PKC) which directly phosphorylates the receptor. We recently found that mild activation of NMDA receptors-with low concentrations of NMDA-potentiates mGluR5-mediated responses by reversing this agonist-induced desensitization. Interestingly, stronger activation of NMDA receptors reduced mGluR5-mediated responses and increased mGluR5 phosphorylation. This is especially interesting in light of recent studies that suggest that low frequency stimulation of glutamatergic afferents to hippocampal area CA1 induces preferential activation of the protein phosphatase calcineuron whereas high frequency stimulation leads to activation of PKC and a net increase in protein phosphorylation. Based on this and a number of other previous studies, we postulated that the differential effects of different concentrations of NMDA on mGluR5 are mediated by net increases and decreases in mGluR5 phosphorylation. Furthermore, we postulate that low frequency stimulation of glutamatergic afferents induces preferential dephosphorylation of mGluR5 and potentiates mGluR5-mediated responses whereas high frequency stimulation induces a net increase in mGluR5 phosphorylation and inhibition of mGluR5-mediated responses. A combination of molecular, biochemical and electrophysiological techniques will be used to directly test these hypotheses.