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首页> 外文学位 >Regulation of alpha7 nicotinic acetylcholine receptor function and pharmacology by amino acid sequence in the second transmembrane domain.
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Regulation of alpha7 nicotinic acetylcholine receptor function and pharmacology by amino acid sequence in the second transmembrane domain.

机译：通过第二跨膜结构域中的氨基酸序列调节α7烟碱型乙酰胆碱受体功能和药理作用。

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摘要

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels with clearly defined physiological roles at the neuromuscular junction and in peripheral ganglia, and more mysterious roles in the mammalian brain, and non-neuronal tissues. The larger family of nicotinic receptors can be broadly categorized into three major subgroups based on subunit composition, anatomical distribution, and functional and pharmacological differences. These are the muscle-type receptors, the heteromeric neuronal receptors, and the homomeric receptors, typified by receptors composed of the alpha7 subunit.; Our studies demonstrate that a conferring of a functional phenotype can be accomplished by systematic substitution of amino acid sequence from the beta subunits of either muscle-type (beta1) or neuronal (beta2/beta4) nAChRs into homomeric receptors composed of mutant alpha7 nAChR subunits. Specifically, the alpha7 TM2 T6'F mutant shows properties similar to the muscle-type nAChR with regard to divalent ion permeability, current rectification, agonist concentration-dependent kinetics, sensitivity to succinycholine, and a lack of potentiation by 5-hydroxyindole. While a variety of muscle receptor-like properties are observed in the T6'F mutant, the alpha7 TM2 T6'S mutant, which has amino acid sequence identical to the neuronal beta2/beta4 subunit at this position, demonstrates significant kinetic similarities to neuronal nAChRs, but largely retains the pharmacology of the wild-type alpha7 receptor. At the single-channel level, the T6'S mutant has a unitary conductance similar to that reported for wild-type alpha7, but a vastly longer average open duration. Furthermore, channel burst activity indicates a significantly greater likelihood of channel opening in the sustained presence of agonist relative to wild-type.; The significant impact of these TM2 6' substitutions on a variety of functional aspects of the mutant alpha7 receptors suggests that amino acid sequence at this position contributes to several important features that distinguish the major nAChR subgroups from one another. Furthermore, the alpha7 TM2 T6'S mutant shows a kinetic gain of function in the absence of significant pharmacological differences from the wild-type alpha7 receptor. Thus it may provide the ability to observe agonist-evoked signals using contemporary high-throughput drug screening methods (where the wild-type receptor would be inhibited), implicating it as a potential tool for identifying alpha7-selective compounds.
机译：烟碱乙酰胆碱受体（nAChRs）是五聚体配体门控离子通道，在神经肌肉接头和周围神经节具有明确定义的生理作用，在哺乳动物脑和非神经元组织中的作用更为神秘。更大的烟碱受体家族可根据亚基组成，解剖分布以及功能和药理学差异大致分为三个主要亚组。这些是肌肉型受体，异源神经元受体和同型受体，以α7亚基组成的受体为代表。我们的研究表明，可以通过将氨基酸序列从肌肉型（beta1）或神经元（beta2 / beta4）nAChRs的β亚基系统置换为由突变体alpha7 nAChR亚基组成的同型受体来实现功能表型的赋予。具体来说，alpha7 TM2 T6'F突变体在二价离子渗透性，电流整流，激动剂浓度依赖性动力学，对琥珀胆碱的敏感性以及缺乏5-羟吲哚的增强作用方面显示出与肌肉型nAChR相似的特性。尽管在T6'F突变体中观察到了多种类似于肌肉受体的特性，但在此位置具有与神经元beta2 / beta4亚基相同的氨基酸序列的alpha7 TM2 T6'S突变体与神经元nAChRs表现出显着的动力学相似性，但是在很大程度上保留了野生型α7受体的药理作用。在单通道水平上，T6'S突变体具有与野生型alpha7相似的单一电导，但平均开放时间长得多。此外，相对于野生型，在持续存在激动剂的情况下，通道爆发活性表明通道打开的可能性明显更大。这些TM2 6'取代对突变体alpha7受体的各种功能方面的重大影响表明，此位置的氨基酸序列具有几个重要特征，这些特征将主要的nAChR亚组彼此区分开。此外，在没有与野生型α7受体明显的药理学差异的情况下，α7TM2 T6'S突变体显示出功能的动力学增强。因此，它可以提供使用当代高通量药物筛选方法观察激动剂引起的信号的能力（其中野生型受体会被抑制），暗示它是鉴定α7选择性化合物的潜在工具。

著录项

  • 作者

    Placzek, Andon Nicholas.;

  • 作者单位

    University of Florida.;

  • 授予单位 University of Florida.;
  • 学科 Biology Neuroscience.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 100 p.
  • 总页数 100
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;药理学;
  • 关键词

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