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Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor 烟碱乙酰胆碱受体外源性和内源性非竞争性抑制剂的结合位点
Pub Date : 1998-08-21 DOI: 10.1016/S0304-4157(98)00004-5
Hugo Rubén Arias

The nicotinic acetylcholine receptor (AChR) is the paradigm of the neurotransmitter-gated ion channel superfamily. The pharmacological behavior of the AChR can be described as three basic processes that progress sequentially. First, the neurotransmitter acetylcholine (ACh) binds the receptor. Next, the intrinsically coupled ion channel opens upon ACh binding with subsequent ion flux activity. Finally, the AChR becomes desensitized, a process where the ion channel becomes closed in the prolonged presence of ACh. The existing equilibrium among these physiologically relevant processes can be perturbed by the pharmacological action of different drugs. In particular, non-competitive inhibitors (NCIs) inhibit the ion flux and enhance the desensitization rate of the AChR. The action of NCIs was studied using several drugs of exogenous origin. These include compounds such as chlorpromazine (CPZ), triphenylmethylphosphonium (TPMP+), the local anesthetics QX-222 and meproadifen, trifluoromethyl-iodophenyldiazirine (TID), phencyclidine (PCP), histrionicotoxin (HTX), quinacrine, and ethidium. In order to understand the mechanism by which NCIs exert their pharmacological properties several laboratories have studied the structural characteristics of their binding sites, including their respective locations on the receptor. One of the main objectives of this review is to discuss all available experimental evidence regarding the specific localization of the binding sites for exogenous NCIs. For example, it is known that the so-called luminal NCIs bind to a series of ring-forming amino acids in the ion channel. Particularly CPZ, TPMP+, QX-222, cembranoids, and PCP bind to the serine, the threonine, and the leucine ring, whereas TID and meproadifen bind to the valine and extracellular rings, respectively. On the other hand, quinacrine and ethidium, termed non-luminal NCIs, bind to sites outside the channel lumen. Specifically, quinacrine binds to a non-annular lipid domain located ∼7 Å from the lipid–water interface and ethidium binds to the vestibule of the AChR in a site located ∼46 Å away from the membrane surface and equidistant from both ACh binding sites. The non-annular lipid domain has been suggested to be located at the intermolecular interfaces of the five AChR subunits and/or at the interstices of the four (M1–M4) transmembrane domains. One of the most important concepts in neurochemistry is that receptor proteins can be modulated by endogenous substances other than their specific agonists. Among membrane-embedded receptors, the AChR is one of the best examples of this behavior. In this regard, the AChR is non-competitively modulated by diverse molecules such as lipids (fatty acids and steroids), the neuropeptide substance P, and the neurotransmitter 5-hydroxytryptamine (5-HT). It is important to take into acco

烟碱乙酰胆碱受体(AChR)是神经递质门控离子通道超家族的典范。AChR的药理学行为可以描述为三个基本过程,这些过程依次进行。首先,神经递质乙酰胆碱(ACh)与受体结合。接下来,内在耦合的离子通道在ACh结合时打开,随后具有离子通量活性。最后,乙酰胆碱还原酶变得脱敏,这是一个离子通道在乙酰胆碱的长期存在下变得关闭的过程。这些生理相关过程之间的现有平衡可能被不同药物的药理作用所扰乱。特别是,非竞争性抑制剂(nci)抑制离子通量,提高AChR的脱敏率。用几种外源药物研究了NCIs的作用。这些化合物包括氯丙嗪(CPZ)、三苯基甲基膦(TPMP+)、局部麻醉剂QX-222和甲丙二芬、三氟甲基碘苯二嗪(TID)、苯环利定(PCP)、组氨酸毒素(HTX)、奎宁和乙啶。为了了解NCIs发挥其药理学特性的机制,几个实验室研究了它们结合位点的结构特征,包括它们在受体上的各自位置。本综述的主要目的之一是讨论所有关于外源性nci结合位点特异性定位的现有实验证据。例如,众所周知,所谓的腔内NCIs与离子通道中的一系列环状氨基酸结合。特别是CPZ、TPMP+、QX-222、类膜膜和PCP结合丝氨酸、苏氨酸和亮氨酸环,而TID和甲proadifen分别结合缬氨酸和细胞外环。另一方面,被称为非管腔NCIs的阿奎宁和乙啶,与通道管腔外的位点结合。具体来说,醌与位于脂水界面~ 7 Å处的非环状脂质结构域结合,乙啶与位于距膜表面~ 46 Å处的乙酰胆碱受体前庭结合,与两个乙酰胆碱结合位点的距离相等。非环状脂质结构域被认为位于5个AChR亚基的分子间界面和/或4个(M1-M4)跨膜结构域的间隙。神经化学中最重要的概念之一是受体蛋白可以被内源性物质而不是其特异性激动剂调节。在膜嵌入受体中,AChR是这种行为的最好例子之一。在这方面,AChR受多种分子的非竞争性调节,如脂质(脂肪酸和类固醇)、神经肽物质P和神经递质5-羟色胺(5-HT)。重要的是要考虑到上述调制是通过这些内源性分子与AChR的直接结合产生的。由于这是一个生理学相关的问题,阐明每个内源性NCI结合位点的结构成分是有用的。在这方面,这项工作的另一个重要目的是回顾所有与内源性nci结合位点具体定位相关的现有信息。例如,已知神经递质物质P和5-HT都与离子通道的管腔结合。特别是,P物质的位点位于δM2结构域,而5-HT和相关化合物的结合位点被推测位于丝氨酸和苏氨酸环上。相反,脂肪酸和类固醇分子与非腔内位点结合。更具体地说,脂肪酸可以结合到围绕着AChR膜内周长的带状结构,即环状脂质结构域,和/或位于非环状脂质结构域的高亲和喹啉位点。此外,类固醇可能与位于AChR细胞外亲水结构域和/或脂质-蛋白界面的位点结合。具体来说,在环状脂质结构域或靠近非环状醌结合位点。乙酰胆碱在毫摩尔浓度下的自抑制作用也可以被认为是乙酰胆碱受体功能调节的内源性机制。对激动剂自我抑制位点定位的研究表明,非常高浓度的激动剂可能结合到离子通道(一个腔内位点)和/或结合到奎宁位点(一个非腔内位点)。 考虑到参与NCI结合的AChR的某些结构域决定了所研究配体的功能作用,腔内和非腔内结合位点的存在支持了NCI至少有两种不同作用机制的观点:一种是药物阻碍离子渗透的立体机制,另一种是变构过程,在配体结合后,乙酰胆碱受体发生构象变化,导致离子通道关闭,从而阻碍离子流动。
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引用次数: 99
Phases and phase transitions of the phosphatidylcholines 磷脂酰胆碱的相和相变
Pub Date : 1998-06-29 DOI: 10.1016/S0304-4157(98)00006-9
Rumiana Koynova , Martin Caffrey

LIPIDAT (http://www.lipidat.chemistry.ohio-state.edu) is an Internet accessible, computerized relational database providing access to the wealth of information scattered throughout the literature concerning synthetic and biologically derived polar lipid polymorphic and mesomorphic phase behavior and molecular structures. Here, a review of the data subset referring to phosphatidylcholines is presented together with an analysis of these data. This subset represents ca. 60% of all LIPIDAT records. It includes data collected over a 43-year period and consists of 12,208 records obtained from 1573 articles in 106 different journals. An analysis of the data in the subset identifies trends in phosphatidylcholine phase behavior reflecting changes in lipid chain length, unsaturation (number, isomeric type and position of double bonds), asymmetry and branching, type of chain–glycerol linkage (ester, ether, amide), position of chain attachment to the glycerol backbone (1,2- vs. 1,3-) and head group modification. Also included is a summary of the data concerning the effect of pressure, pH, stereochemical purity, and different additives such as salts, saccharides, amino acids and alcohols, on phosphatidylcholine phase behavior. Information on the phase behavior of biologically derived phosphatidylcholines is also presented. This review includes 651 references.

LIPIDAT (http://www.lipidat.chemistry.ohio-state.edu)是一个可在互联网上访问的计算机化关系数据库,提供了大量关于合成和生物衍生的极性脂质多形性和中形性相行为和分子结构的文献信息。在这里,回顾的数据子集涉及磷脂酰胆碱与这些数据的分析一起提出。这个子集约占所有LIPIDAT记录的60%。它包括在43年期间收集的数据,包括从106个不同期刊的1573篇文章中获得的12,208条记录。对该亚组数据的分析确定了磷脂酰胆碱相行为的趋势,反映了脂链长度、不饱和(双键的数目、异构体类型和位置)、不对称和分支、链-甘油键的类型(酯、醚、酰胺)、链与甘油主链的连接位置(1,2-对1,3-)和头基修饰的变化。还包括有关压力、pH、立体化学纯度和不同添加剂(如盐、糖、氨基酸和醇)对磷脂酰胆碱相行为影响的数据摘要。生物来源的磷脂酰胆碱的相行为的信息也提出。本综述包括651篇参考文献。
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引用次数: 932
P-type calcium ATPases in higher plants – biochemical, molecular and functional properties 高等植物p型钙三磷酸腺苷酶的生化、分子和功能特性
Pub Date : 1998-06-29 DOI: 10.1016/S0304-4157(97)00009-9
David E. Evans , Lorraine E. Williams
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引用次数: 77
Microtubule-based membrane movement 基于微管的膜运动
Pub Date : 1998-06-29 DOI: 10.1016/S0304-4157(97)00010-5
Jon Lane , Viki Allan
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引用次数: 95
Polarized trafficking of plasma membrane proteins: emerging roles for coats, SNAREs, GTPases and their link to the cytoskeleton 质膜蛋白的极化运输:衣壳、SNAREs、gtp酶的新角色及其与细胞骨架的联系
Pub Date : 1998-06-29 DOI: 10.1016/S0304-4157(98)00005-7
Benjamin Aroeti, Hana Okhrimenko, Vanda Reich, Ena Orzech
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引用次数: 58
The influenza virus hemagglutinin: a model protein in the study of membrane fusion 流感病毒血凝素:膜融合研究中的模型蛋白
Pub Date : 1998-06-29 DOI: 10.1016/S0304-4157(98)00002-1
João Ramalho-Santos , Maria C. Pedroso de Lima
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引用次数: 29
A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems 膜的计算机视角:脂质双分子层系统的分子动力学研究
Pub Date : 1997-11-21 DOI: 10.1016/S0304-4157(97)00008-7
D.P Tieleman, S.J Marrink, H.J.C Berendsen
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引用次数: 679
Ligand conduction and the gated-pore mechanism of transmembrane transport 配体传导和跨膜运输的门孔机制
Pub Date : 1997-11-21 DOI: 10.1016/S0304-4157(97)00007-5
Ian C West
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引用次数: 55
Influence of pH gradients on the transbilayer transport of drugs, lipids, peptides and metal ions into large unilamellar vesicles pH梯度对药物、脂质、多肽和金属离子进入大单层囊泡的跨双层转运的影响
Pub Date : 1997-09-08 DOI: 10.1016/S0304-4157(97)00006-3
Pieter R Cullis , Michael J Hope , Marcel B Bally , Thomas D Madden , Lawrence D Mayer , David B Fenske
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引用次数: 208
Surface plasmon resonance spectroscopy as a tool for investigating the biochemical and biophysical properties of membrane protein systems. I: Theoretical principles 表面等离子体共振光谱作为研究膜蛋白系统的生化和生物物理性质的工具。一、理论原理
Pub Date : 1997-09-08 DOI: 10.1016/S0304-4157(97)00004-X
Zdzislaw Salamon , H.Angus Macleod , Gordon Tollin
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引用次数: 202
期刊
Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes
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