mGluR-Homer interactions in excessive drinking

mGluR-Homer 与过量饮酒的相互作用

基本信息

批准号：
7291085
负责人：
Karen Kathleen Szumlinski
金额：
$ 15.55万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7291085
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase 7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester Acute Alcohol Phenotype Alcohol consumption Alcoholism Alcohols Amino Acids Architecture Attenuated Behavioral Binding Boutos Brain Breeding Cell membrane Chromosome Pairing Chronic Co-Immunoprecipitations Cocaine Collaborations Complementary DNA Complex Data Dendritic Spines Dependovirus Development Diglycerides Disease Disruption Dopamine Dose Down-Regulation Drosophila genus Enhancers Etiology Event Exhibits Family Gene Expression Genes Genetic Germany Glutamate Receptor Glutamates Health Sciences Heavy Drinking Heritability Home environment Homer protein Human Immunoblotting Indiana Infusion procedures Inositol Isoenzymes Knock-in Mouse Knockout Mice LY294002 Laboratories Laser Scanning Microscopy Localized Mediating Mediator of activation protein Membrane Messenger RNA Metabotropic Glutamate Receptors Modeling Molecular Morphology Motivation Motor Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neuronal Plasticity Neurons Nucleus Accumbens Numbers Olives - dietary Oregon Personal Communication Pharmaceutical Preparations Phenotype Phospholipase C Phosphotransferases Photons Play Principal Investigator Proline Protein Family Proteins RNA Interference RNA Splicing Receptor Activation Regulation Research Research Personnel Rodent Role Scaffolding Protein Schedule Screening procedure Series Shipping Ships Signal Transduction Site Small Interfering RNA Structure Subfamily lentivirinae Synapses Synaptic plasticity Testing Texas Tissues Transfection Transgenic Mice Universities Variant Welts alcohol effect austin base density design drinking drinking behavior drinking water gene interaction in vivo insight kinase inhibitor medical schools member metabotropic glutamate receptor type 1 neuroadaptation neurochemistry neuropsychiatry neurotransmission novel postsynaptic programs protein expression receptor receptor expression receptor function research study theories tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): Current theories of alcoholism posit that alcohol-induced neuroadaptations within limbic structures in the brain, including the nucleus accumbens (NAC), contribute to the transition from recreational alcohol drinking to excessive alcohol consumption. Recently, the Group 1 metabotropic glutamate receptor (mGluR) associated scaffolding protein Homer2 was identified as an active and necessary cellular mediator of alcohol-induced neural plasticity in mice. Constitutively expressed Homer proteins facilitate Group 1 mGluRstimulated intracellular signaling and cluster Group 1 mGluRs within the postsynaptic density, co-localizing these receptors with other proteins implicated in synaptic plasticity, such as PI3K (phosphatiylionsitol-3 kinase). Homer2 deletion reduces the function and the expression of Group 1 mGluRs in the NAC in vivo and the alcohol-avoiding and -intolerant behavioral phenotype of Homer2 knock-out (KO) mice resembles that produced by the pharmacological blockade of Group 1 mGluRs. Collectively, these observations suggest that Group 1 mGluR-Homer signaling is an important cellular mediator of excessive alcohol consumption. To test this hypothesis directly, this proposal will employ in vivo pharmacological and genetic approaches to characterize the role for Group 1 mGluR-Homer signaling within the NAC in regulating excessive alcohol consumption within the scheduled high alcohol consumption (SHAC) murine model (Aim 1). Immunohistochemical and immunoblotting approaches will be employed to determine the role for Homer2 n regulating the effects of sustained, excessive alcohol consumption upon the synaptic architecture of NAC neurons, as well as the formation, subcellular localization and function of mGluR-Homer signaling complexes (Aim 2). Finally, to relate genetic variance in excessive alcohol drinking to mGluR-Homer-PI3K expression and signaling within the NAC, immunoblotting the total protein content and membrane localization of members of the mGluR-Homer-PI3K signaling cascade will be compared between mouse lines selectively bred for high SHAC and SLAC (Scheduled Low Alcohol Consumption) phenotypes. The results of these studies will further our understanding of the cellular mechanisms involved in regulating the transition from recreational to excessive alcohol drinking and provide greater insight into the etiology of alcoholism and its treatment.

描述（由申请人提供）：当前的酗酒理论认为，酒精诱导的大脑边缘结构（包括伏隔核（NAC））内的神经适应有助于从娱乐性饮酒到过度饮酒的转变。最近，1 类代谢型谷氨酸受体 (mGluR) 相关支架蛋白 Homer2 被确定为小鼠酒精诱导神经可塑性的活性且必需的细胞介质。组成型表达的 Homer 蛋白促进第 1 组 mGluR 刺激的细胞内信号传导，并将第 1 组 mGluR 在突触后密度内聚集，使这些受体与其他涉及突触可塑性的蛋白质（例如 PI3K（磷酸肌醇 3 激酶））共定位。 Homer2 缺失降低了体内 NAC 中第 1 组 mGluR 的功能和表达，Homer2 敲除 (KO) 小鼠的回避和不耐受行为表型与第 1 组 mGluR 的药理学阻断所产生的行为表型相似。总的来说，这些观察结果表明第 1 组 mGluR-Homer 信号传导是过度饮酒的重要细胞介质。为了直接检验这一假设，本提案将采用体内药理学和遗传学方法来表征 NAC 内第 1 组 mGluR-Homer 信号在调节预定高酒精消耗 (SHAC) 小鼠模型中过量饮酒中的作用（目标 1）。将采用免疫组织化学和免疫印迹方法来确定 Homer2 n 对持续过量饮酒对 NAC 神经元突触结构的影响的调节作用，以及 mGluR-Homer 信号复合物的形成、亚细胞定位和功能（目标 2））。最后，为了将过量饮酒的遗传变异与 NAC 内的 mGluR-Homer-PI3K 表达和信号传导联系起来，将在选择性繁殖的小鼠系之间比较 mGluR-Homer-PI3K 信号级联成员的总蛋白含量和膜定位的免疫印迹适用于高 SHAC 和 SLAC（计划性低酒精消耗）表型。这些研究的结果将进一步加深我们对调节从娱乐性饮酒到过度饮酒的转变所涉及的细胞机制的理解，并为酗酒的病因及其治疗提供更深入的了解。