P2X2和P2X4受体的调制位点

P2X受体是非选择性阳离子通道,广泛分布于中枢及外周神经系统。近年来,本实验室侧重研究重金属、质子、酒精等对P2X2和P2X4受体的调制。研究发现不同的因素对同一种受体介导的ATP-激活电流有不同的调制作用,如增强效应、抑制效应或者两种效应兼有,而且同一种因素对这两种受体的调制效应也不相同。因此,我们推测P2X受体上存在不同的结合位点,本文主要阐述P2X2和P2X4受体不同的调制位点。     

P2X受体研究进展

P2X受体为配体门控离子通道,属于P2受体家族。P2X受体的配体是ATP,胞外ATP结合时P2X受体通道打开,允许阳离子(Na 、Ca2 等)通过。目前已克隆了7个哺乳动物的P2X(P2X1-7)受体,并阐明了它们的药理学特性。天然P2X受体可以组装成同型或异型聚合体,形成功能性离子通道。对有关P2X受体的结构、分布、功能、生物物理学特性等研究的最新进展进行了综述。     

P2X嘌呤受体及其调制

嘌呤受体可分为Ｐ１（腺苷）和Ｐ２（ＡＴＰ）受体,在后者的诸亚型中仅Ｐ２Ｘ受体属配体门控离子通道受体超家族成员,Ｐ２Ｙ受体及其它亚型均为Ｇ蛋白偶联受体。本文介绍有关Ｐ２Ｘ嘌呤受体的特性,功能及其调制,包括变构性和胞内磷酸化调制。     

Bone phenotype of P2X4 receptor knockout mice: implication of a P2X7 receptor mutation?

Transgenic and knockout animal models are widely used to investigate the role of receptors, signaling pathways, and other peptides and proteins. Varying results are often published on the same model from different groups, and much effort has been put into understanding the underlying causes of these sometimes conflicting results. Recently, it has been shown that a P2X4R knockout model carries a so-called passenger mutation in the P2X7R gene, potentially affecting the interpretation of results from studies using this animal model. We therefore report this case to raise awareness about the potential pitfalls using genetically modified animal models, especially within P2 receptor research. Although purinergic signaling has been recognized as an important contributor to the regulation of bone remodeling, the process that maintains the bone quality during life, little is known about the role of the P2X4 receptor (P2X4R) in regulation of bone remodeling in health and disease. To address this, we analyzed the bone phenotype of P2rx4tm1Rass (C57BL/6J) knockout mice and corresponding wildtype using microCT and biomechanical testing. Overall, we found that the P2X4R knockout mice displayed improved bone microstructure and stronger bones in an age- and gender-dependent manner. While cortical BMD, trabecular BMD, and bone volume were higher in the 6-month-old females and 3-month-old males, this was not the case for the 3-month-old females and the 6-month-old males. Bone strength was only affected in the females. Moreover, we found that P2X4R KO mice carried the P2X7 receptor 451P wildtype allele, whereas the wildtype mice carried the 451L mutant allele. In conclusion, this study suggests that P2X4R could play a role in bone remodeling, but more importantly, it underlines the potential pitfalls when using knockout models and highlights the importance of interpreting results with great caution. Further studies are needed to verify any specific effects of P2X4R on bone metabolism.

     

P2X7受体与炎性细胞因子

P2X7受体是嘌呤受体中功能独特的一个亚型,为ATP控制的离子通道,在单核细胞、巨噬细胞、中性粒细胞中高表达,被ATP激活后导致K＋外流和Ca^2＋内流、非选择性膜孔形成,启动一系列信号途径如炎症小体NALP3的活化,丝裂原蛋白激酶途径激活NF-κB增强炎性细胞因子转录,ROS和氮介质的产生,介导IL-1β、IL-6、IL-18、TNF-α、MIP-2、CCL2、HMGB1等多种炎性细胞因子的释放,参与炎症的发生发展,与真菌感染及阿尔茨海默病、类风湿性关节炎、哮喘等炎症性疾病密切相关.     

中枢神经系统离子通道受体P2X7的研究进展

在ATP门控离子通道P2X受体家族中,P2X7受体由于在结构和功能上与其他(P2X1-P2X6)受体的显著差别而备受关注.P2X7受体是由3个同源亚基组成的多聚体,其C端为P2X受体家族中最长的,与其他已知蛋白没有同源性.P2X7受体具有独特的双功能性,被ATP激活后形成非选择性阳离子通道,允许钾、钠、钙等阳离子跨膜流动,而对二价阳离子表现出相对较强的选择性,在低浓度二价阳离子环境及ATP的持续刺激下,激活的P2X7受体能形成大的孔通道.P2X7受体广泛分布在血液系统、免疫系统和骨组织等多种组织器官中,通过信号转导参与细胞增殖、蛋白合成和细胞凋亡等事件.近年来在中枢神经系统中的研究发现,P2X7受体参与神经突触传递等生理过程,并在神经性退变等病理过程中发挥重要的调节作用.其中,多种假说支持它与少突胶质细胞的损伤有密切关系.     

P2X4受体的结构功能关系研究进展

嘌呤能受体P2X4是三磷酸腺苷(ATP)-门控的阳离子通道,对生物体内多种重要生命活动起一定的调节作用。二次跨膜的三聚体通道P2X4受体的三维空间组成是由胞外结构域、跨膜域及胞内N-、C-端组成。ATP的三磷酸基团能被位于亚基界面的ATP结合口袋的带正电氨基酸特异性识别,嘌呤环则被疏水氨基酸和部分氨基酸的主链氧所识别。P2X4受体激活后,胞外阳离子更多是通过侧窗路径进入细胞内。就P2X4受体的空间结构、配体的识别、离子通透途径及门控机制作一综述。     

P2X7受体与炎症性肠病

P2X7受体与炎症密切相关,且在肠道细胞广泛表达。动物实验表明,ATP/P2X7信号主要介导加重肠炎,众多细胞参与这一作用,包括巨噬细胞、树突状细胞、T细胞、肥大细胞以及肠道神经元等。也有证据表明在弓形虫引起的肠炎中,P2X7信号则发挥抑制炎症的作用,其具体机制还有待进一步研究。本文就P2X7受体与炎症性肠病(inflammatory bowel disease,IBD)的相关研究进展作一综述,希望能为P2X7受体与IBD的进一步研究提供指导和借鉴。     

P2X7受体与炎症相关性疾病

P2X7是一种在多种免疫细胞中广泛表达的以ATP为配体的阳离子通道受体,它的激活能引起和加重炎症反应。当细胞处于损伤、缺氧或炎症状态时, P2X7受体可被释放到胞外的大量ATP激活,进而通过活化NLRP3炎症小体、调节基因转录等方式,影响炎症介质(IL-1β、IL-18等)的释放从而参与多种炎症性疾病,如糖尿病肾病、系统性红斑狼疮(systemic lupus erythematosus,SLE)等。近年来,细胞外ATP-P2X7受体信号通路已成为炎症性疾病研究较多的通路之一。大量研究表明, P2X7受体是治疗炎症性疾病的潜在靶点。该文将对P2X7受体及其参与的炎症相关性疾病的关系作一综述。     

P2X7受体与疾病的相关性

P2X受体是一类离子型配体门控通道,分为7个不同的亚型(P2X1～7)。嘌呤能离子通道型受体7(purinergic ligand-gated ion channel 7 receptor, P2X7R)是ATP门控的,非选择性的阳离子通道,属于嘌呤受体P2X家族。P2X7受体广泛表达于神经系统、肌肉组织和免疫系统。在胞外ATP作用下,P2X7受体偶联多种胞内信号通路,参与细胞增殖、凋亡及炎症因子的释放等多种生理功能。研究发现,P2X7受体与诸多疾病有着密切联系,包括自身免疫性疾病(如关节炎和炎症性肠病)、神经退行性疾病、慢性疼痛、情绪障碍和癌症等。P2X7受体异常表达会导致这些疾病的发生,增加疾病的易感性与病变程度。现就P2X7受体的生物学特征、P2X7受体与疾病的关系及其特异性阻断剂和激动剂进行综述。     

嘌呤能受体P2X3的调控机理

P2X受体是由胞外ATP激活的配体型门控阳离子通道,其亚型P2X3受体在咳嗽、疼痛、高血压等疾病的发生过程中发挥重要作用,以P2X3受体为药物靶标开展研究对疾病的治疗有重要意义。该文就P2X3受体的结构、激活剂及抑制剂的作用机理展开综述。     

Temporal Interleukin-1�� Secretion from Primary Human Peripheral Blood Monocytes by P2X7-independent and P2X7-dependent Mechanisms

The processing and regulated secretion of IL-1β are critical points of control of the biological activity of this important pro-inflammatory cytokine. IL-1β is produced by both monocytes and macrophages, but the rate and mechanism of release differ according to the differentiation status and the origin of these cells. We aimed to study the control of processing and release in human blood monocytes and human monocyte-derived macrophages. Toll-like receptor (TLR)-induced IL-1β production and release were investigated for dependence upon caspase-1, P2X7 receptor activation, and loss of membrane asymmetry associated with microvesicle shedding. TLR agonists induced P2X7 receptor-dependent IL-1β release in both monocytes and macrophages; however, only monocytes also showed P2X7 receptor-independent release of mature IL-1β. Furthermore, in monocytes ATP-mediated PS exposure could be activated independently of IL-1β production. Release of IL-1β from monocytes showed selectivity for specific TLR agonists and was accelerated by P2X7 receptor activation. Human monocytes released more IL-1β/cell than macrophages. These data have important implications for inflammatory diseases that involve monocyte activation and IL-1 release.     

离子通道受体P2X4的结构及生物学功能

P2X4受体是P2X受体家族的成员。目前,已从人、大鼠、小鼠、鸡胚和非洲爪蟾的组织中获得了全长cDNA。P2X4受体分布广泛,在被ATP及其同系物激活后,引起细胞内钙离子浓度显升高,将信号传递给下游的信号分子。     

P2X受体调节剂的作用机制与最新研究进展

ATP激活的配体门控阳离子通道P2X受体参与多种生理病理功能,是一类重要的新药靶标。目前发现的多种靶向P2X受体的小分子药物多数因结果未达到预期或存在明显的副作用而止步于临床研究。明确的调节机制可为靶向P2X受体的理性药物设计提供新的方向,从而提高药物发现概率和有效性。本文就P2X受体调节剂的作用机制进行综述,并对靶向P2X受体的小分子药物最新研究进展进行总结。     

P2X3受体在感觉神经节的表达

用免疫组织化学与原位杂交研究P2X3受体在背根神经节,三叉神经节和结状神经节的分布。结果显示：1、原位杂交;在三种感觉神经节中,95%左右的神经节细胞为P2X3mRNA阳性,中、小型神经节细胞的杂交信号一般要比大型的神经节细胞强一些,2、免疫组织化学;免疫组织化学结果与原位杂交结果基本一致。此外,在各神经节内,均显示出许多P2X3免疫阳性神经纤维,在足掌表皮也显示许多P2X3免疫反应阳性纤维,结果提示：P2X3不仅参与机体的痛觉的形成,还可能参与其它感觉,如本体感觉等的形成。     

非洲爪蟾卵母细胞P2X受体存在的证明

目的：D1中除有P2Y受体介导的成分外,可能还有P2X受体介导的电流参与。本研究的目的在于进一步证实D1电流中是否有P2X受体介导电流的存在。方法：采用双电极电压钳记录方法。结果：Zn^2＋对不依赖于G蛋白之IATP（D1）具有增强作用;重复施加ATP Dl电流逐步减小,而D2电流则逐步增大。在仅有D12之IATP（D2）情况下,重复加ATP后D2电流不但不增大反而有所下降。结论：非洲爪蟾卵母细胞上存在P2X受体。     

P2X7受体在病理性疼痛中的研究进展

病理性疼痛主要包括组织损伤或炎症引起的炎症痛、神经系统损伤或疾病引起的神经病理性疼痛和恶性肿瘤及治疗引起的癌症痛三大类。病理性疼痛对常规的镇痛药物反应不理想,迫切需要寻找新的对病理性疼痛更有效和更特异的治疗手段。P2X7受体作为离子通道型嘌呤能受体,在炎症痛、神经病理性疼痛和癌症痛中都具有重要作用。靶向P2X7受体的新药物将为病理性疼痛的治疗带来新的希望。该文综述了P2X7受体在三类病理性疼痛中的研究进展。     

Opposite effects of P2X7 and P2Y2 nucleotide receptors on α-secretase-dependent APP processing in Neuro-2a cells

The amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases to release amyloid-β peptide (Aβ), the main component found in senile plaques of Alzheimer's disease (AD) patient brains. Alternatively, APP can be cleaved within the Aβ sequence by α-secretase, thus precluding the generation of Aβ. We have demonstrated that activation of the P2X7 receptor leads to a reduction of α-secretase activity in Neuro-2a cells. Moreover, the P2X7 ligand 2'(3')-O-(4-benzoylbenzoyl) ATP (BzATP) can also activate a different P2 receptor in these cells. This receptor, whose pharmacology resembles that of the P2Y(2) receptor, has an opposite effect, leading to increases in α-secretase activity. Our study suggests that P2X7R and P2Y(2)R could be novel therapeutic targets in AD.     

The role of the P2X₇ receptor in infectious diseases

ATP is an extracellular signal for the immune system, particularly during an inflammatory response. It is sensed by the P2X₇ receptor, the expression of which is upregulated by pro-inflammatory cytokines. Activation of the P2X₇ receptor opens a cation-specific channel that alters the ionic environment of the cell, activating several pathways, including (i) the inflammasome, leading to production of IL-1β and IL-18; (ii) the stress-activated protein kinase pathway, resulting in apoptosis; (iii) the mitogen-activated protein kinase pathway, leading to generation of reactive oxygen and nitrogen intermediates; and (iv) phospholipase D, stimulating phagosome-lysosome fusion. The P2X₇ receptor can initiate host mechanisms to remove pathogens, most particularly those that parasitise macrophages. At the same time, the P2X₇ receptor may be subverted by pathogens to modulate host responses. Moreover, recent genetic studies have demonstrated significant associations between susceptibility or resistance to parasites and bacteria, and loss-of-function or gain-of-function polymorphisms in the P2X₇ receptor, underscoring its importance in infectious disease.     

P2X受体在CCI模型中介导疼痛的研究进展

神经病理痛是临床上常见病症,对人身心健康危害较大,其发病机制尚不清楚,目前无有效的治疗手段,加之慢性神经病理痛持续时间长,其研究成为疼痛领域的热点和重点.本文将围绕着P2X受体在CCI模型中介导疼痛方面的研究加以归纳和总结.