肿瘤化疗与药物代谢酶遗传多态性的关系

遗传药理学(Pharrnacogenetics)是研究机体遗传变异引起的药物反应异常的一门新兴学科。遗传药理学研究表明，遗传是药物在人体内的处置与机体对之产生反应的决定因素，是产生药物代谢与反应个体差异的重要原因。具体表现为药物代谢酶和(或)受体表达的改变，而药物代谢酶的多态性似乎比受体多态性更常见。     

与类风湿关节炎相关的G蛋白偶联受体及治疗药物作用靶点

很多胞外信号直接或间接通过G蛋白偶联受体向胞内传输。多种G蛋白偶联受体包括趋化因子受体、前列腺素(prostaglandins,PGs)受体、β2-肾上腺素受体(β2-adrener-gicreceptor)、致炎肽P物质(proinflammatorypeptidesub-stanceP,SP)受体、蛋白酶活化受体2(protease-activatedre-ceptor2,PAR-2)等在免疫应答调节中起至关重要的作用。该文综述了与类风湿关节炎相关的G蛋白偶联受体(Gpro-tein-coupledreceptors,GPCRs)信号转导的一些蛋白作用,包括G蛋白偶联受体激酶、视紫红质抑制蛋白(arrestin)、G蛋白信号转导调节因子、G蛋白偶联致炎受体等。作用于这些信号或其转导过程的药物正成为类风湿关节炎治疗的新策略之一。     

肿瘤化疗与药物代谢酶遗传多态性的关系

遗传药理学(Pharmacogenetics)是研究机体遗传变异引起的药物反应异常的一门新兴学科.遗传药理学研究表明,遗传是药物在人体内的处置与机体对之产生反应的决定因素,是产生药物代谢与反应个体差异的重要原因[1].具体表现为药物代谢酶和(或)受体表达的改变,而药物代谢酶的多态性似乎比受体多态性更常见[2].……     

G-蛋白偶联受体的功能测定和高通量药物筛选

G 蛋白偶联受体家族是药物开发中最大的一类药物靶点 ,高通量药物筛选是开发药物早期阶段的最重要工具之一。根据G 蛋白偶联受体与配体结合及激发的信号通路 ,人们设计了各种可行的功能测试方法 ,用于G 蛋白偶联受体为药靶的高通量药物筛选 ,如 :微体积荧光数字图像测定技术 (Fluorometicmicrovolumeassaytechnology ,FMAT)、荧光偏振 (Fluoresencepolarization ,FP)、竞争性ELISA (Com petitiveenzyme linkedimmunosorbent)、闪烁邻近测定法(Scintillation proximityassay ,SPA)、载黑色素细胞测定法(Melanophoreassay)、报告基因测定法 (Reportergeneassay)和钙离子测定法等测定方法。在这些方法中 ,报告基因测定法和钙离子测定法占了主导地位。非放射性、无需底物和辅助剂的报告基因测定方法和荧光钙离子指示剂的钙离子测定方法可能是将来G 蛋白偶联受体的功能分析和高通量药物筛选的发展方向     

G蛋白偶联受体固有活性研究进展与新药开发

G蛋白偶联受体(G-prote in-coup led receptor,GPCR)是与G蛋白有信号连接的一大类受体家族,是人体内最大的膜受体蛋白家族,是一类具有7个跨膜螺旋的跨膜蛋白受体。GPCR的结构特征和在信号传导中的重要作用决定了其可以作为很好的药物靶标。目前世界药物市场上有三分之一的小分子药物是GPCR的激活剂(agon ist)或拮抗剂(antagon ist)。以其为靶点的药物在医药产业中占据显著地位。在当今前50种最畅销的上市药物中,20%属于G蛋白受体相关药物。近来的研究发现,大多数G蛋白偶联受体具有一个很重要的特性,就是具有固有活性(Constitutive ac-tivity),即无激动剂条件受体自发的维持激活并维持下游信号传导通路的活性。固有活性涉及受体、G蛋白及下游信号通路之间的关系。该文就G蛋白偶联受体固有活性概念、研究进展、反相激动剂与固有活性研究、固有活性与新药开发4个方面,进行以下论述。     

代谢性谷氨酸受体药理学研究进展

代谢性谷氨酸受体是一组G是蛋白偶联的受体家族,各种亚型在中枢神经系统的分布、分子生物学和药理学特征不同。代谢性谷氨酸受体可以广泛精细调节神经系统功能。药理学研究发现,该受体与许多中枢系统疾病发病机制有关,在脑缺血、神经元坏死和凋亡、癫痫、精神分裂症、焦虑等方面具有成为药物作用靶点的潜力。     

β-肾上腺素受体遗传多态性与疾病易感性及药物反应差异的关系

β-肾上腺素受体是G蛋白偶联受体的一个亚家族，它们以儿茶酚胺为内源性配体，介导机体的重要生理功能；同时，β-肾上腺素受体也是许多药物的作用靶点。本文重点阐述β-肾上腺素受体常见的遗传多态性与疾病易感性及药物反应差异的关系。     

细胞核G蛋白偶联受体研究进展

传统观念认为,G蛋白偶联受体通过自身在细胞表面的激活启动信号转导,从而介导细胞响应外界刺激。近年来研究发现了细胞核G蛋白偶联受体（nGPCR）的存在,有别于细胞质膜G蛋白偶联受体（mGPCR）,细胞核G蛋白偶联受体具有独特的来源、功能、信号途径和作用模式。本文总结了目前对于细胞核G蛋白偶联受体的研究成果,以期为靶向G蛋白偶联受体的药物研发提供新的理念和思路。     

M受体及相关选择性药物研究进展

毒草碱受体（M受体）是体内重要的G蛋白偶联受体之一,有M1～M5五种药理学亚型,各亚型在体内的分布和功能不同,受体蛋白结构和信号转导机制也有差异。对M受体、相关选择性药物及受体一配体作用位点的研究,将为设计以M受体各亚型为靶标的选择性药物提供帮助,对临床治疗多种M受体功能紊乱的疾病,如阿尔茨海默病等具有重要意义。     

G蛋白偶联雌激素受体在雌激素相关肿瘤发生中的作用

在经典的雌激素核受体α和β之外,雌激素或雌激素样物质也可以经过膜受体,即G蛋白偶联雌激素受体(GPER)发挥功能。G蛋白偶联雌激素受体是雌激素非基因通路信号转导过程的重要介导因子,在雌激素相关肿瘤细胞的发生和治疗中具有重要的意义。现针对G蛋白偶联雌激素受体在雌激素相关肿瘤细胞中介导的效应及有关机制的研究进展进行综述。     

CCK receptor polymorphisms: an illustration of emerging themes in pharmacogenomics

Polymorphisms in G-protein-coupled receptors can alter drug affinity and/or activity. In addition, genetic differences in amino acid sequences can induce ligand-independent signaling, which in turn can lead to disease. With growing efforts in the field of pharmacogenomics, it is anticipated that polymorphism-induced alterations in drug and/or receptor function will be a focus of increasing concern during the course of future drug-development efforts. In this review, the spectrum of pharmacological consequences that result from polymorphisms in the cholecystokinin CCK2 receptor will be discussed, thereby illustrating emerging themes in pharmacogenomics.     

New prospects for drug discovery from structural studies of rhodopsin

G-protein-coupled receptors (GPCR) are a major class of membrane proteins belonging to a continuously growing superfamily. These receptors play a critical role in signal transduction, and are among the most important pharmacological drug targets. The first structural model for the GPCR superfamily was the bacterial protein bacteriorhodopsin with its characteristic seven transmembrane (TM) helical architecture. The visual photoreceptor rhodopsin is a better model for GPCR, and the recent elucidation of the crystal structure of bovine rhodopsin has renewed the interest in this receptor as a template for molecular modeling of other GPCR, particularly for the implications in ligand design and drug discovery. In this work different specific structural elements of rhodopsin are reviewed and the role of conserved motifs, like those associated with receptor function, is analyzed. The specific characteristics of the membrane-embedded ligand-binding domain are described. Other aspects, like receptor dimerization or the constitutive activity mechanism, are also outlined. The importance of acquiring knowledge of the active conformation of the receptor by means of both modeling and experimental techniques is also highlighted. In this regard, the model of the activated form of rhodopsin is currently under investigation, and it may provide useful information for pharmaceutical design. Rhodopsin will continue to be a widely used model for GPCR but rhodopsin-based approaches have to be complemented by other theoretical and experimental approaches -while waiting for the crystal structure of other members of the superfamily- if these want to be successfully used for drug discovery.     

G蛋白偶联受体组成性活性及反向激动剂研究进展

G蛋白偶联受体（GPCR）是受体中家族成员最多的一大类，其活性涉及体内绝大部分的生理功能，在药物研发过程中是主要的药物作用靶标。研究表明，GPCR及其突变体在缺乏配体结合的情况下，能自发地产生一定程度的内在活性，即GPCR的组成性活性（constitutive activity）；其相应的反向激动剂与GPCR结合能降低受体的组成性活性，在药物治疗学上具有重要意义。愈来愈多的实验表明，GPCR组成性活性及反向激动剂的研究具有广阔和实际的应用前景，对其进行深入研究在受体学说领域和药物研发过程中具有重要理论意义。     

Heterodimerisation of G protein-coupled receptors: implications for drug design and ligand screening

Importance of the field: In recent times many G protein-coupled receptors (GPCRs) have been shown to dimerise/oligomerise and, in some cases, such structural organization has been found to be essential for receptor function or to play a modulatory role in living cells. The fact that these complexes may display differential pharmacology through, for example, the formation of a new binding pocket or signalling properties, as well as different functions or regulation in physiological tissues, offers novel opportunities for drug discovery. As a consequence, it seems necessary to develop new approaches suitable for GPCR heterodimer identification and selective ligand screening. Areas covered in this review: This review gives an overview of new strategies that have been developed in an effort to incorporate the possibilities added by GPCR hetero-oligomerisation on the screening of compounds as drug candidates. What the reader will gain: The reader will gain a wider knowledge about how the current understanding of GPCR oligomeric structure and function has mandated that hetero-oligomeric receptors must be considered as novel targets in the identification of future lead compounds. Take home message: For the improvement of novel drug discovery, more structural and functional information on the process of receptor oligomerisation is needed, and the realisation that the function of GPCRs can be greatly influenced by other interacting receptors or proteins also demands consideration in the lead-compound developing process in order to achieve better therapeutic agents.     

Regulation of G protein-coupled receptor signalling: focus on the cardiovascular system and regulator of G protein signalling proteins

G protein-coupled receptors (GPCRs) are involved in many biological processes. Therefore, GPCR function is tightly controlled both at receptor level and at the level of signalling components. Well-known mechanisms by which GPCR function can be regulated comprise desensitization/resensitization processes and GPCR up- and downregulation. GPCR function can also be regulated by several proteins that directly interact with the receptor and thereby modulate receptor activity. An additional mechanism by which receptor signalling is regulated involves an emerging class of proteins, the so-called regulators of G protein signalling (RGS). In this review we will describe some of these control mechanisms in more detail with some specific examples in the cardiovascular system. In addition, we will provide an overview on RGS proteins and the involvement of RGS proteins in cardiovascular function.     

基因多态性对地高辛代谢影响的研究进展

地高辛作为临床上治疗充血性心力衰竭的经典药物,因其作用持久、价格低廉且不容易产生耐药现象,广泛地用于各种急慢性心功能不全、室上性心动过速、心房扑动及心房颤动等疾病的治疗。因地高辛的治疗浓度接近中毒浓度,如何在其狭窄的治疗窗内提高疗效,保证安全有效地应用地高辛,一直是临床亟待解决的问题。近年来,对地高辛的药物基因组学研究发现,某些基因位点的多态性可影响地高辛的药物代谢及作用,从而部分解释了患者对地高辛有效剂量的个体差异。本文就近年来涉及的地高辛药物基因组学研究进行综述,以期为地高辛的个体化用药提供参考。     

GPCR偏向性配体介导的选择性功能

G蛋白偶联受体(GPCR)是当今药物治疗中最有效靶向作用的受体超家族之一,它在人类的正常生理状态和疾病过程中都发挥着极大的功效。近年研究发现,GPCR脱敏作用的调节器β-arrestin,可作为真正的衔接蛋白将信号转导到多重效应途径。β-arrestin介导的信号对生化和功能方面的影响力都不同于传统G蛋白介导的信号。由此发现辨别出的多种G蛋白-偏向配体或β-arrestin偏向配体,不仅是用来研究GPCR信号生化特征的有效工具,还具有被开发成治疗药物的潜力。因此,该文就偏向性配体的特点、作用机制、药理学作用及研究偏向性配体的技术进行综述。