核受体与脂质代谢

核受体是配体活化的转录因子,能调控大量的靶基因。近年来核受体调节脂质代谢的研究已成为国内外研究的热点。由于核受体在调节脂质代谢、糖代谢以及炎症反应方面发挥重要作用,它们是治疗心血管疾病理想的靶标。本文简要地介绍了核受体在调节脂质代谢方面的研究进展。     

孤啡肽受体的配体研究进展

孤啡肽(nociceptin或orphanin FQ)发现于1995年底, 它是阿片受体样受体(ORL1或LC 132) 的内源性配体,在痛觉调节、心血管系统、离子通道、依赖和耐受、学习和记忆等方面具有广泛的生物学活性. 最近几年, 对孤啡肽受体与相关配体构效关系的研究成为一个新的热点.对在研究构效关系过程中所发现的孤啡肽受体相关配体（片段、拮抗剂、激动剂、部分激动剂和阻断剂）的研究情况进行了介绍.     

Eph受体家族及其配体的信号转导途径及功能

Eph受体是已知最大的酪氨酸蛋白激酶受体家族,Eph受体和其膜附着型配体（ephrin）在发育过程中呈现不同的表达模式,近来研究证明,Eph受体和其配体在包括神经网络形成,神经管和轴旁中胚层的成型（patterning）,细胞迁移导向和轴突路径导引,血管形成等许多的发育过程中起重要作用.Eph受体及其配体也与肿瘤发生有关,因此深入分析这些分子尤其在肿瘤细胞生长中的功能而应用于治疗具有重要的临床意义.     

核受体Rev-Erbα与代谢及心血管疾病

人类生理过程呈现24小时的生物节律,其受时钟基因控制和调节。细胞核受体Rev-Erbα是生物钟系统的重要组成部分,不仅是生物钟基因而且是生物钟调节基因,在维持生物节律准确性中发挥着重要作用;同时,Rev-Erbα调节糖代谢、脂质代谢、脂肪形成、纤溶蛋白降解、血管炎症并与其他与能量平衡相关核受体相互作用参与动脉粥样硬化发生发展过程。以往认为Rev-Erbα是一种孤儿受体,但最近发现其配体是血红素,这一发现拓宽了对该基因的理解并使其成为新的药物靶点。本文提出Rev-Erbα作为生物节律、代谢、免疫调节的共同节点,参与代谢疾病和心血管疾病的过程;并就最新研究进展进行了综述。     

雌激素受体ERα的功能调控及相关疾病的研究进展

雌激素受体(estrogen receptorα,ERα)是依赖配体活化转录因子的核受体家族成员之一,参与靶细胞的增殖和分化。ERα活化的经典途径是与雌激素结合后直接作用于靶基因上游的雌激素受体反应元件(ERE),从而诱导靶基因转录。雌激素受体的功能受许多因子调节,包括与之结合的配体、DNA上的顺式元件、募集的辅助调节因子及细胞环境等。在雌激素受体相关疾病中,除乳腺癌和子宫内膜癌外,近年研究表明心血管疾病、骨质疏松症、阿尔茨海默氏病等疾病也与雌激素受体密切相关。雌激素的生物效应与多种疾病的发生、转归和预后密切相关。本文将综述几类辅助调节因子对雌激素受体介导的基因转录的调控,雌激素受体相关疾病,及环境有害物质对ERα功能的影响。     

尿激酶／尿激酶受体结构研究进展

尿激酶是纤溶酶原的主要激活物之一。近年来的研究工作发现,尿激酶及其受体-尿激酶受体-在其他多种生理和病理过程中也发挥了重要作用,包括了创伤愈合、组织再生、细胞迁移、特别是癌症转移和血管生成等多种生理和病理过程。除了其配体尿激酶外,尿激酶受体还能结合其他多种蛋白质,包括了玻璃体结合蛋白、LDL受体蛋白,及多种整合素等蛋白质,这些蛋白质-蛋白质相互作用是尿激酶-尿激酶受体系统生物作用的结构基础,是目前的一个重要研究方向。结合作者的工作描述了该体系的结构研究现状。     

血浆中的可溶性受体

可溶性受体的来源大致分为膜受体的胞外段经水解酶水解释放、基因选择性拼接、病毒基因的表达、人工基因重组。可溶性受体的作用机制包括作为相应膜受体的竞争者阻断配体的信号转导,作为血清结合蛋白转运、稳定、富集配体,下调膜受体数量,上调配体效应等。其临床应用主要是作为某些疾病的监测指标和相应细胞因子的拮抗剂。     

β-肾上腺素受体调节蛋白及其功能

血管疾病成为威胁人类健康头号杀手,心血管受体在心血管疾病的发生、发展及预防和治疗中具有举足轻重的地位。β-肾上腺素受体作为G蛋白偶联受体家族的成员,是心血管药物最重要的靶点之一。β-肾上腺素受体阻滞剂被认为是继洋地黄后药物防治心脏疾病的最伟大突破,其在心血管领域的研究和应用一直是被关注的热点。2012年度诺贝尔化学奖再次授予了β-肾上腺素受体的研究。随着研究的深入,人们发现β-肾上腺素受体接受着细胞内调控蛋白的精密调控,不同调控蛋白介导着受体不同的生理信号通路和病理性信号通路。基于这些发现,近年来提出了受体功能选择性的配体药物,这也将成为未来药物的研究方向。本文综述了β-肾上腺素受体调节蛋白及相关信号通路及功能。     

异源物代谢核受体PXR和CAR在血管疾病中的作用

孕烷X受体(pregnant X receptor,PXR)和组成型雄甾烷受体(constitutive androstane receptor,CAR)是核受体(nuclear receptors,NRs)超家族的重要成员,主要分布在肝脏和小肠等组织,经配体激活后可调控药物代谢酶及转运体的表达和活性,调节毒性物质的清除、解毒及代谢,保护机体免受外源性化学物质和内源性毒性脂质损伤。因此,PXR和CAR也被称为异源物代谢核受体(xenobiotic nuclear receptors)。近年发现,PXR和CAR也参与糖、脂代谢和炎症等信号通路的调控,同时,在血管内皮细胞也有表达,从而可能与动脉粥样硬化、高血压等血管疾病的发生密切相关。本文简要综述PXR和CAR的结构、组织分布、配体、激活及其在血管疾病中的作用。     

糖尿病相关VPAC、PAC受体及其药物研发的进展

VPAC、PAC受体是近年发现的开发2型糖尿病药物的重要靶标,垂体腺苷酸环化酶激活多肽(PACAP)、血管活性肠肽(VIP)则是它们的天然配体,与受体结合激活后能促进葡萄糖依赖性胰岛素分泌,既能保护细胞又不引起胰高血糖素分泌和糖原分解,因此其配体相关化合物的开发研究成为开发2型糖尿病药物的重要方向。目前针对VPAC、PAC受体开发的配体类似物主要包括了肽类和非肽类小分子两大类,但它们仍然存在诸多不足,至今仅有一个药物进入到临床研究阶段。本综述系统总结了目前针对VPAC、PAC受体为靶标的肽类和非肽小分子药物的开发研究现状,可为将来此类药物的研发提供参考。     

细胞受体与疾病的相关性研究进展

受体是存在于效应细胞中的重要功能蛋白，它和配体具有高亲和力，受体异常亦称受体病，拟就近年来细胞受体和受体病的研究进展作一综述。     

Novel receptor partners and function of receptor activity-modifying proteins

The receptor activity-modifying proteins (RAMPs) comprise a family of three accessory proteins that heterodimerize with the calcitonin receptor-like receptor (CL receptor) or with the calcitonin receptor (CTR) to generate different receptor phenotypes. However, RAMPs are more widely distributed across cell and tissue types than the CTR and CL receptor, suggesting additional roles for RAMPs in cellular processes. We have investigated the potential for RAMP interaction with a number of Class II G protein-coupled receptors (GPCRs) in addition to the CL receptor and the CTR. Using immunofluorescence confocal microscopy, we demonstrate, for the first time, that RAMPs interact with at least four additional receptors, the VPAC1 vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor with all three RAMPs; the glucagon and PTH1 parathyroid hormone receptors with RAMP2; and the PTH2 receptor with RAMP3. Unlike the interaction of RAMPs with the CL receptor or the CTR, VPAC1R-RAMP complexes do not show altered phenotypic behavior compared with the VPAC1R alone, as determined using radioligand binding in COS-7 cells. However, the VPAC1R-RAMP2 heterodimer displays a significant enhancement of agonist-mediated phosphoinositide hydrolysis with no change in cAMP stimulation compared with the VPAC1R alone. Our findings identify a new functional consequence of RAMP-receptor interaction, suggesting that RAMPs play a more general role in modulating cell signaling through other GPCRs than is currently appreciated.     

Coupling of agonist-induced AMPA receptor internalization with receptor recycling

Excitatory post-synaptic currents in the CNS are primarily mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors in response to glutamate. Internalization of cell-surface receptors has been shown to be one mechanism by which to control receptor function. To test for agonist control of AMPA receptor plasma membrane expression we used biochemical assays to study AMPA receptor internalization and insertion processes. In heterologous cells, we observed a slow constitutive internalization and a rapid agonist-induced internalization of AMPA receptors. To our surprise, however, agonist treatment had no effect on the steady-state levels of AMPA receptors on the cell surface. To examine whether this could be explained by an agonist-induced increase in the insertion rate of AMPA receptors into the plasma membrane we developed an assay to independently measure receptor insertion. Remarkably, agonist treatment of cells also dramatically increased AMPA receptor plasma membrane insertion rates. In addition, using an assay to measure recycling of internalized pools we found that internalized receptors are rapidly recycled to the cell surface. These results suggest that agonist-induced receptor internalization is coupled to increases in receptor recycling. This increase in receptor flux through intracellular pools may allow for rapid changes in receptor surface expression by independent regulatory control of internalization and insertion.     

Acetylcholine receptor: effects of proteolysis on receptor metabolism

Previous studies (Miskin, R., T. G. Easton, and E. Reich, 1970, Cell. 15:1301-1312) have shown that sarcoma virus transformation and tumor promoters reduced the cell surface concentration of acetylcholine receptors (AChR) in differentiating chick embryo myogenic cultures. Both of these agents also induced high rates of plasminogen activator (PA) synthesis in myogenic cultures (Miskin, R., T. G. Easton, A. Maelicke, and E. Reich, 1978, Cell. 15:1287-1300), and the present work was performed to establish whether proteolysis might significantly affect receptor metabolism. Proteolysis in myogenic cultures was modulated by one or more of the following: stimulation of PA synthesis, direct addition of plasmin, removal of plasminogen, or addition of plasmin inhibitors. The results were: (a) When the rates of proteolysis were raised either by addition of plasmin or by stimulating PA synthesis in the presence of plasminogen, both the steady-state concentration and the half-life of surface AChR decreased, but the rate of receptor synthesis was unaffected. (b) The magnitude of these effects, and their dependence on added plasminogen, indicated that proteolysis initiated by plasminogen activation could account almost entirely for the reduction in receptor half-life produced by sarcoma virus transformation and phorbol ester. (c) The rate of receptor synthesis, which is also reduced by viral transformation and tumor promoters, was not modified by proteolysis; hence plasmin action may be responsible for a large part, but not all of the change in surface receptor under these conditions. (d) The plasmin catalysed changes in receptor parameters appear to occur in response to modified membrane metabolism resulting from proteolysis of surface components other than AChR itself.     

Phosphorylation of brain muscarinic receptor: evidence of receptor regulation

Muscarinic receptor, from porcine synaptic membrane, was purified by affinity chromatography. Molecular weight analysis by SDS-gel electrophoresis revealed one major peptide with an apparent Mr of 68 +/- 2 Kda. The purified receptor was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase resulting in a concomitant loss in specific binding, and this loss was reversed by calcineurin.     

Control of epidermal growth factor receptor endocytosis by receptor dimerization, rather than receptor kinase activation

Given that ligand binding is essential for the rapid internalization of epidermal growth factor receptor (EGFR), the events induced by ligand binding probably contribute to the regulation of EGFR internalization. These events include receptor dimerization, activation of intrinsic tyrosine kinase activity and autophosphorylation. Whereas the initial results are controversial regarding the role of EGFR kinase activity in EGFR internalization, more recent data suggest that EGFR kinase activation is essential for EGFR internalization. However, we have shown here that inhibition of EGFR kinase activation by mutation or by chemical inhibitors did not block EGF-induced EGFR internalization. Instead, proper EGFR dimerization is necessary and sufficient to stimulate EGFR internalization. We conclude that EGFR internalization is controlled by EGFR dimerization, rather than EGFR kinase activation. Our results also define a new role for EGFR dimerization: by itself it can drive EGFR internalization, independent of its role in the activation of EGFR kinase.     

Deorphanization of Dresden G protein-coupled receptor for an odorant receptor

Dresden G protein-coupled receptor (D-GPCR) is one of orphan G protein-coupled receptors (GPCR). Here we report the identification of the ligands and the characterization of D-GPCR. We investigated over 5000 compounds to evoke the response mediated by D-GPCR and identified 3-methyl-valeric acid and 4-methyl-valeric acid as agonists using a cAMP assay. It is of interest that they dramatically enhanced the intracellular cAMP accumulation and the CRE-luciferase activity in CHO-K1 cells and HEK293 cells expressing the chimeric protein of D-GPCR with a rhodopsin-tag at its N-terminus. Our results established new characteristics of D-GPCR as an olfactory receptor. First, agonists of D-GPCR belong to odorants. Second, D-GPCR mRNA is expressed in the olfactory bulb. In addition, D-GPCR was reported to have similar sequences and its genome locus nearby other olfactory receptors. These results suggest D-GPCR is an olfactory receptor.