FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES

海马在许多正常的生理过程和各种病理状况中起着重要作用，包括阿尔茨海默病和颞叶癫痫。 发展一个完整的理解参与调节海马功能的分子和细胞机制可能会导致这些疾病的治疗新策略。直到最近，人们还认为谷氨酸（海马中主要的兴奋性神经递质）的所有作用都是通过激活配体门控阳离子通道来介导的。然而，现在清楚的是，谷氨酸也激活代谢型谷氨酸受体（mGluR），其通过GTP结合蛋白偶联到效应系统。mGluRs在调节海马中的细胞兴奋性和突触传递中起许多重要作用。 一个完整的理解正常和病理海马功能将需要一个详细的了解的作用mGluRs在调节海马生理和参与调节信号的分子机制，这一重要的受体家族的成员。通过分子克隆已鉴定出八种m（GluR）亚型（mGluR 1-mGluR 8）。在海马体中，证据表明mGluR 2、mGluR 7和mGluR 8都位于突触前谷氨酸能神经末梢上，在那里它们可以用于抑制谷氨酸释放。然而，mGluR 7和mGluR 8在调节特定海马突触传递中的假定作用尚未明确确立。 我们最近报道mGluR介导的谷氨酸释放调节可以被蛋白激酶C（PKC）的激活所抑制。然而，目前，PKC抑制突触前mGluRs信号转导的机制尚不清楚。提出了一系列研究，其中结合解剖学、药理学和遗传学方法来严格检验mGluR 7和mGluR 8作为两个主要海马突触的突触前受体的假设。然后，我们将采用生物化学，电生理和分子的方法来严格测试的假设，PKC的激活抑制突触前mGluRs的功能，直接磷酸化的受体和抑制受体偶联GTP结合蛋白。这些研究可能会导致一个根本性的进步，在我们的理解参与调节海马功能的机制，并可能有重要的影响，新的方法来治疗疾病，涉及海马的病理变化。

The hippocampus plays an important role in a number of normal physiological processes and in a variety of pathological conditions, including Alzheimer's disease and temporal lobe epilepsy. Development of a complete understanding of the molecular and cellular mechanisms involved in regulation of hippocampal function could lead to new strategies for treatment of these disorders. Until recently, it was thought that all of the actions of glutamate, the major excitatory neurotransmitter in the hippocampus, were mediated by activation of ligand-gated cation channels. However, it is now clear that glutamate also activates metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. mGluRs play a number of important roles in regulating cell excitability and synaptic transmission in the hippocampus. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in modulating hippocampal physiology and the molecular mechanisms involved in regulating signaling by members of this important receptor family. Eight m(GluR subtypes (mGluR1 - mGluR8) have been identified by molecular cloning. In the hippocampus, evidence suggests that m(GluR2, mGluR7 and mGluR8 are all localized on presynaptic glutamatergic nerve terminals where they may serve to inhibit glutamate release. However, the postulated roles of mGluR7 and mGluR8 in regulating transmission at specific hippocampal synapses have not been definitively established. We recently reported that mGluR- mediated regulation of glutamate release can be inhibited by activation of protein kinase C (PKC). However, at present, the mechanism by which PKC inhibits signaling by presynaptic mGluRs is not known. A series of studies is proposed in which a combination of anatomical, pharmacological, and genetic approaches will be used to rigorously test the hypothesis that mGluR7 and m(GluR8 serve as presynaptic receptors at two major hippocampal synapses. We will then employ biochemical, electrophysiological, and molecular approaches to rigorously test the hypothesis that activation of PKC inhibits the function of presynaptic mGluRs by directly phosphorylating the receptors and inhibiting receptor coupling to GTP binding proteins. These studies could lead to a fundamental advance in our understanding of the mechanisms involved in regulation hippocampal function and could have important implications regarding novel approaches to treatment of disorders involving pathological changes in the hippocampus.