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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Mice expressing the ADNFLE valine 287 leucine mutation of the ??2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function
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Mice expressing the ADNFLE valine 287 leucine mutation of the ??2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function

机译：表达Adnfle缬氨酸的小鼠287亮氨酸突变的荧光乙酰胆碱受体亚单位显示器对急性尼古丁给药的敏感性增加，并且改变了突触前烟碱受体功能

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摘要

Several mutations in ??4 or ??2 nicotinic receptor subunits are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). One such missense mutation in the gene encoding the ??2 neuronal nicotinic acetylcholine receptor (nAChR) subunit (CHRNB2) is a valine-to-leucine substitution in the second transmembrane domain at position 287 (??2VL). Previous studies indicated that the ??2VL mutation in mice alters circadian rhythm consistent with sleep alterations observed in ADNFLE patients (Xu et al., 2011). The current study investigates changes in nicotinic receptor function and expression that may explain the behavioral phenotype of ??2VL mice. No differences in ??2 mRNA expression were found between wild-type (WT) and heterozygous (HT) or homozygous mutant (MT) mice. However, antibody and ligand binding indicated that the mutation resulted in a reduction in receptor protein. Functional consequences of the ??2VL mutation were assessed biochemically using crude synaptosomes. A gene-dose dependent increase in sensitivity to activation by acetylcholine and decrease in maximal nAChR-mediated [ 3H]-dopamine release and 86Rb efflux were observed. Maximal nAChR-mediated [3H]-GABA release in the cortex was also decreased in the MT, but maximal [3H]-GABA release was retained in the hippocampus. Behaviorally both HT and MT mice demonstrated increased sensitivity to nicotine-induced hypolocomotion and hypothermia. Furthermore, WT mice display only a tonic-clonic seizure (EEG recordable) 3 min after injection of a high dose of nicotine, while MT mice also display a dystonic arousal complex (non-EEG recordable) event 30 s after nicotine injection. Data indicate decreases in maximal response for certain measures are larger than expected given the decrease in receptor expression. ? 2012 Elsevier Inc. All rights reserved.
机译：在β4或烟碱受体亚基中的几个突变与常染色体显性夜间瓣膜癫痫（ADNFLE）连接。在编码的基因中的一个这样的畸形突变在编码的α0神经元氰基乙酰胆碱受体（NACHR）亚基（CHRNB2）是在第二跨膜结构域处的缬氨酸 - 亮氨酸取代在287（Δθ2V1）。以前的研究表明，小鼠的2VL突变改变了昼夜节律，其含有Adnfle患者的睡眠改变（XU等人，2011）。目前的研究研究了烟碱受体功能和表达的变化，其可以解释2VL小鼠的行为表型。在野生型（WT）和杂合（HT）或纯合突变体（MT）小鼠之间发现了2 mRNA表达的差异。然而，抗体和配体结合表明突变导致受体蛋白质的还原。使用粗突触骨折评估2VL突变的功能后果。通过乙酰胆碱激活的基因 - 剂量依赖性增加，并观察到最大NACHR介导的最大介导的[3H] - 丁胺释放和86RB流出的降低。 MT的最大NACHR介导的[3H] -Gaba释放在MT中也降低，但最大[3H] -Gaba释放保留在海马中。行为上，HT和MT小鼠都表现出对尼古丁诱导的低气球和体温过低的敏感性。此外，在注射高剂量的尼古丁后，WT小鼠仅显示滋补克隆癫痫发作（EEG可记录）3分钟，而MT小鼠也显示尼古丁注射后的透析唤起复合物（非EEG可记录）事件30s。数据表明某些措施的最大响应的降低大于预期，这给予受体表达的降低。还2012年elsevier Inc.保留所有权利。

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    ONeillH.C.; LavertyD.C.; PatzlaffN.E.; CohenB.N.; FonckC.; McKinneyS.; McIntoshJ.M.; LindstromJ.M.; LesterH.A.; GradyS.R.; MarksM.J.;

  • 作者单位

    Institute for Behavioral Genetics 447 UCB University of Colorado 1480 30th St. Boulder CO;

    Institute for Behavioral Genetics 447 UCB University of Colorado 1480 30th St. Boulder CO;

    Institute for Behavioral Genetics 447 UCB University of Colorado 1480 30th St. Boulder CO;

    Department of Biology California Institute of Technology 1200 E. California Ave Pasadena CA;

    Department of Biology California Institute of Technology 1200 E. California Ave Pasadena CA;

    Department of Biology California Institute of Technology 1200 E. California Ave Pasadena CA;

    Departments of Biology and Psychiatry University of Utah 257S 1400 E Salt Lake City UT 84112;

    Department of Neuroscience Institute for Neurological Science University of Pennsylvania;

    Department of Biology California Institute of Technology 1200 E. California Ave Pasadena CA;

    Institute for Behavioral Genetics 447 UCB University of Colorado 1480 30th St. Boulder CO;

    Institute for Behavioral Genetics 447 UCB University of Colorado 1480 30th St. Boulder CO;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Autoradiography; Autosomal dominant nocturnal frontal lobe epilepsy; Knock-in mouse; Nicotine; Nicotinic acetylcholine receptor; Synaptosomes;

    机译：autoradoography;常染色体显性夜间叶癫痫;敲击小鼠;尼古丁;烟碱乙酰胆碱受体;突触体;

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