Expression and Function of the Alpha 7 Nicotinic Receptor in Schizophrenia

描述（由申请人提供）： 17神经元烟碱乙酰胆碱受体基因（CHRNA 7）是精神分裂症的复制候选基因，在炎症和应激中也具有保护作用。来自该基因的蛋白质亚基（17）与其他四个类似亚基组装形成五聚体功能性17* 受体，其具有五个激动剂结合位点。17* 受体是精神分裂症认知缺陷药物开发的重要靶点。激动剂刺激导致通道打开和一价和二价阳离子（包括Ca++）进入，导致突触前神经递质释放和突触后在突触后密度（PSD）处的调节以及基因表达的下游变化。CHRNA 7的结构很复杂;它作为嵌合基因（CHRFAM 7A）部分复制。表达嵌合体CHRFAM 7A。最近的数据表明，CHRFAM 7A作为CHRNA 7结合和功能的显性负调控因子。CHRFAM 7A中的2bp缺失与精神分裂症相关，并导致CHRNA 7功能进一步降低。精神分裂症患者具有低水平的17* 受体，如通过配体[125 I]-1-银环蛇毒素（I-BTX）的结合所测量的。这些患者大多数是重度吸烟者。与对照组相比，精神分裂症非吸烟者的mRNA和蛋白质减少，但在大多数吸烟者中，mRNA和蛋白质水平正常。因此，精神分裂症患者中I-BTX结合的低水平不能用CHRNA 7 mRNA或蛋白质表达来解释。我们推测，重复的基因，CHRFAM 7A，作为一个显性负调节，减少17* 受体的表面结合和功能。目前的提案将表征CHRFAM 7A基因的结构，表达和调控，并研究其与全长基因CHRNA 7的相互作用。 公共卫生相关性： 退伍军人中精神分裂症的患病率约为10%，远高于一般人群。成瘾，特别是尼古丁，更高，退伍军人约35%，而普通人群为22%。吸烟和精神分裂症密切相关，因为超过80%的精神分裂症患者吸烟，可能是自我治疗的一种形式。尼古丁受体与精神分裂症和吸烟有关。17* 烟碱乙酰胆碱受体是精神分裂症中的一个复制候选基因，在精神分裂症脑中表达减少，并在尼古丁成瘾中起作用。受体基因CHRNA 7的部分重复调节其功能。该提案将在分子水平上表征部分重复CHRFAM 7A，并研究其在精神分裂症中的表达。拟议的研究将有助于开发额外的17* 受体靶向药物用于认知。

DESCRIPTION (provided by applicant): The 17 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a replicated candidate gene for schizophrenia and is also protective in inflammation and stress. The protein subunit (17), derived from the gene, assembles with four other like subunits to form the pentameric, functional 17* receptor, which has five agonist-binding sites. The 17* receptor is an important target in drug development for cognitive deficits in schizophrenia. Agonist stimulation results in opening of the channel and entry of mono- and divalent cations, including Ca++, leading presynaptically to neurotransmitter release and postsynaptically to regulation at the post-synaptic density (PSD) and to down-stream changes in gene expression. Structure of CHRNA7, is complex; it is partially duplicated as a chimeric gene (CHRFAM7A). The chimera, CHRFAM7A, is expressed. Recent data suggests that CHRFAM7A acts as a dominant negative regulator of CHRNA7 binding and function. A 2bp deletion in CHRFAM7A is associated with schizophrenia and results in further decreasing CHRNA7 function. Schizophrenic patients have low levels of 17* receptors, as measured by binding of the ligand [125I]-1-bungarotoxin (I-BTX). Most of these patients are heavy cigarette smokers. The mRNA and protein in schizophrenic non-smokers is reduced compared to controls, but in the majority of subjects who smoke, there are normal levels of mRNA and protein. Thus, the low levels of I-BTX binding in schizophrenic patients are not explained by CHRNA7 mRNA or protein expression. We hypothesize that the duplicated gene, CHRFAM7A, acting as a dominant negative regulator, decreases the surface binding and function of 17* receptors. The current proposal will characterize the structure, expression and regulation of the CHRFAM7A gene and investigate its interaction with the full-length gene, CHRNA7. PUBLIC HEALTH RELEVANCE: The prevalence of schizophrenia is approximately 10% in Veterans, much higher than in the general population. Addiction, particularly to nicotine, is higher, ~35% in Veterans compared to 22% in the general population. Smoking and schizophrenia are intimately related since more than 80% of schizophrenics smoke, possibly as a form of self-medication. Nicotinic receptors are involved in both schizophrenia and smoking. The 17* nicotinic acetylcholine receptor, a replicated candidate gene in schizophrenia, is decreased in expression in schizophrenic brain and plays a role in nicotine addiction. A partial duplication of the receptor gene, CHRNA7, regulates its function. This proposal will characterize the partial duplication, CHRFAM7A, at the molecular level and study its expression in schizophrenia. The proposed research will contribute to development of additional 17* receptor-targeted drugs for cognition.