G蛋白偶联受体激酶活性调控与细胞炎性损伤

G蛋白偶联受体激酶 (Gprotein coupledreceptorki nases,GRKs)不仅调节G蛋白偶联受体 (GPCR)磷酸化、介导受体脱敏 ,使信号效应降低或消失 ,而且也调节G蛋白和靶细胞骨架 ,同时它还受到蛋白激酶A(PKA)、蛋白激酶C(PKC)、肌动蛋白和细胞内第二信使钙离子等调节。组织细胞表面存在多种GPCR如血小板活化因子 (PAF)受体、组胺受体、凝血酶受体等 ,介导炎性介质所致细胞损伤的信号转导作用。GRKs磷酸化GPCR ,在炎症诱导细胞损伤过程中起一定调控作用     

G蛋白偶联受体激酶和arrestins在受体调节中的作用

Ｇ 蛋白偶联受体（ Ｇｐｒｏｔｅｉｎ ｃｏｕｐｌｅｄ ｒｅｃｅｐｔｏｒ ， Ｇ Ｐ Ｃ Ｒｓ）是一大家族，介导许多激素的信号转导。在激动剂的持续作用下， Ｇ Ｐ Ｃ Ｒｓ 可发生对激动剂的敏感性下降，即受体减敏，现认为这一过程主要由 Ｇ 蛋白偶联受体激酶（ Ｇｐｒｏｔｅｉｎ ｃｏｕ ｐｌｅｄ ｒｅｃｅｐｔｏｒ ｋｉｎａｓｅｓ ， Ｇ Ｒ Ｋｓ） 和ａｒｒｅｓｔｉｎｓ 两大蛋白家族介导： Ｇ Ｒ Ｋｓ 先结合并磷酸化被激动剂占领的受体，然后ａｒｒｅｓｔｉｎｓ与磷酸化的受体结合，阻止受体与 Ｇ 蛋白发生作用，导致受体功能减退。近来发现， Ｇ Ｒ Ｋｓ 和ａｒｒｅｓｔｉｎｓ 还参与受体的内陷机制，而受体的复敏又与内陷密切相关     

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。     

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。     

G蛋白偶联受体119激动剂的研究进展

G蛋白偶联受体119 (GPR119)是治疗2型糖尿病有希望的靶点,它既可以直接促进胰岛素的分泌,也能够通过刺激葡萄糖依赖性GIP/CLP-1的释放间接增加胰岛素的分泌,而不引起低血糖。小分子GPR119激动剂具有显著的作用优势,使其成为开发2型糖尿病药物的研究热点之一。本文对近五年基于GPR119靶点的抗糖尿病活性小分子进行综述。     

G蛋白偶联受体在肝细胞癌中调控作用研究进展

G蛋白偶联受体(GPCR),又称为7-α螺旋跨膜蛋白受体,是己知的3类涉及跨膜信号转导的膜受体之一。GPCR与G蛋白结合产生生物学效应,对机体生理功能和病理过程有广泛的调控作用。大量研究表明,GPCR通过调节下游某些信号的转导途径影响肝癌细胞的增殖、侵袭和转移过程,参与肝细胞癌(HCC)的发生和发展。本文就趋化因子受体、前列腺素受体、肾上腺素受体和血管紧张素受体等GPCR及其相关的信号通路在HCC发生发展进程中的作用进行综述,并对靶向GPCR的HCC治疗前景予以展望。     

组成型激活突变体在G蛋白偶联受体研究中的应用

G蛋白偶联受体(GPCR)组成型活性概念的提出，使组成型激活突变体(CAM)成为研究GPCR的新方法。CAM促进了对GPCR的结构、激活机制、活性调节及病理生理的研究。通过对CAM的研究发现了GPCR激活的关键结构区域，提出配体受体相互作用的”扩充的三元复合物模型”和GPCR激活过程中存在多个中间激活态的观点。CAM在一定程度上模拟了野生型受体激活的失敏过程，并为疾病的研究提供新的思路。     

G蛋白偶联受体二聚化研究进展

G蛋白偶联受体(GPCR s)是最大的细胞膜受体家族,具有七螺旋跨膜肽段结构。近年来,越来越多的研究认为这些受体以二聚体的形式参与调节生理活动,对信号识别及转导有重要作用。随着生物技术及分子生物学的发展,GPCRs二聚体研究已取得了很大的进展。该文就这些方面及同源、异源二聚体对受体结合及信号转导的重要作用作一简述。     

G protein-coupled receptor kinases regulate metabotropic glutamate receptor 5 function and expression

Metabotropic glutamate receptors (mGluR) serve important neuromodulatory roles at glutamatergic synapses to shape excitatory neurotransmission. Recent evidence indicates that the desensitization of mGluRs is an important determinant in regulating the functions of these receptors. The present results demonstrate that G protein-coupled receptor kinases (GRKs), which are known to regulate the desensitization of many G protein-coupled receptors, regulate both the expression and function of mGluR5 in a heterologous expression system. This regulatory event is limited to members of the GRK2 family since GRK4 family members do not elicit the same effects on mGluR5. Kinase activity is shown to be required for GRK-mediated regulation of mGluR5. Furthermore, the ability of GRK2 to regulate mGluR5 is dependent, at least in part, on the presence of threonine 840 in the carboxyl terminus of mGluR5. These studies identify novel roles for GRKs in regulating mGluR5 that may serve to further shape the function of these receptors in neurotransmission.     

Non-binding site modulation of G protein-coupled receptor signalling

G protein-coupled receptors (GPCRs) are by far the most successful drug targets yet known, due to their key role in cellular communication. Historically, these drugs bind to the same site at which the endogenous agonist interacts. However, as the details of cell signalling are clarified, it is becoming apparent that there are many other sites at which GPCR signalling can be modulated. Furthermore, the emerging ability to block protein-protein interactions with small molecules means that these sites are now also viable therapeutic targets. Potential points of therapeutic intervention of GPCR signalling are at the level of the G protein, where the activities of both a and βγ subunits could be controlled; at multiple effectors such as the adenylyl cyclases, phospholipases and phosphodiesterases; at regulatory proteins such as the regulators of G protein signalling (RGS) proteins or receptor kinases; or at the mitogenic pathways, which offer many sites for intervention. By targeting these sites, perhaps just one arm of the multiple pathways through which a receptor works can be modified, thus providing a greater degree of therapeutic selectivity and specificity than can be attained using receptor agonists or antagonists.     

G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function

The concept that G protein-coupled receptors (GPCRs) can form hetero-dimers or hetero-oligomers continues to gain experimental support. However, with the exception of the GABA_B receptor and the sweet and umami taste receptors few reported examples meet all of the criteria suggested in a recent International Union of Basic and Clinical Pharmacology sponsored review (Pin et al., 2007) that should be required to define distinct and physiologically relevant receptor species. Despite this, there are many examples in which pairs of co-expressed GPCRs reciprocally modulate their function, trafficking and/or ligand pharmacology. Such data are at least consistent with physical interactions between the receptor pairs. In recent times, it has been suggested that specific GPCR hetero-dimer or hetero-oligomer pairs may represent key molecular targets of certain clinically effective, small molecule drugs and there is growing interest in efforts to identify ligands that may modulate hetero-dimer function selectively. The current review summarizes key recent developments in these topics.     

Morphine-induced physiological and behavioral responses in mice lacking G protein-coupled receptor kinase 6

G protein-coupled receptor kinases (GRKs) are a family of intracellular proteins that desensitize and regulate the responsiveness of G protein-coupled receptors (GPCRs). In the present study, we assessed the contribution of GRK6 to the regulation and responsiveness of the G protein-coupled mu-opioid receptor (μOR) in response to morphine in vitro and in vivo using mice lacking GRK6. In cell culture, overexpression of GRK6 facilitates morphine-induced beta-arrestin2 (βarrestin2) recruitment and receptor internalization, suggesting that this kinase may play a role in regulating the μOR. In vivo, we find that acute morphine treatment induces greater locomotor activation but less constipation in GRK6 knockout (GRK6-KO) mice compared to their wild-type (WT) littermates. The GRK6-KO mice also appear to be “presensitized” to the locomotor stimulating effects induced by chronic morphine treatment, yet these animals do not display more conditioned place preference than WT mice do. Furthermore, several other morphine-mediated responses which were evaluated, including thermal antinociception, analgesic tolerance, and physical dependence, were not affected by ablation of the GRK6 gene. Collectively, these results suggest that GRK6 may play a role in regulating some, but not all morphine-mediated responses. In addition, these findings underscore that the contribution of a particular regulatory factor to receptor function can differ based upon the specific cell composition and physiology assessed, and illustrate the need for using caution when interpreting the importance of interactions observed in cell culture.     

Differences between natural and recombinant G protein-coupled receptor systems with varying receptor/G protein stoichiometry

The increasing accessibility of genetically engineered receptor systems for the study of drug–receptor interaction has led to a corresponding increase in the testing of new drug entities in recombinant receptor systems. In this article Terry Kenakin illustrates some possible conditions within these recombinant systems where the relative stoichiometry of the receptors to other cellular components may differ from that found in natural systems and where this difference may lead to anomalies in drug testing.     

G蛋白偶联受体119激动剂MBX-2982的合成

目的改进G蛋白偶联受体119(GPR119)激动剂MBX-2982的合成工艺。方法以4-氰基哌啶-1-甲酸叔丁酯为起始原料,经过硫代、缩合、醚化、脱Boc保护以及取代反应制得MBX-2982。结果与结论经5步反应合成目标化合物MBX-2982,其结构经1H-NMR及MS谱确证。对多步反应条件进行了工艺考察及优化,总收率为42.8%(以4-氰基哌啶-1-甲酸叔丁酯计),高于文献收率(30.8%)。     

Embracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma

G protein-coupled receptors (GPCRs) regulate numerous airway cell functions, and signaling events transduced by GPCRs are important in both asthma pathogenesis and therapy. Indeed, most asthma therapies target GPCRs either directly or indirectly. Within recent years, our understating of how GPCRs signal and are regulated has changed significantly as new concepts have emerged and traditional ideas have evolved. In this review, we discuss current concepts regarding constitutive GPCR activity and receptor agonism, functional selectivity, compartmentalized signaling, and GPCR desensitization. We further discuss the relevance of these ideas to asthma and asthma therapy, while emphasizing their potential application to the GPCR signaling in airway smooth muscle that regulates airway patency and thus disease severity.