嘌呤P2Y6受体生物学特性最新研究(2)

　　5调节膀胱功能
　　
　　刺激膀胱平滑肌细胞P2Y6受体能通过PLC /IP3信号通路调节膀胱膀胱平滑肌的收缩[20].在麻醉小鼠 体 内，膀胱 上 皮 细 胞通 过 释 放ATP激 活P2Y6受体能提高膀胱的排空频率[21],膀胱上皮细胞是通过泛连接蛋白-1管道释放ATP激活P2Y6受体使膀胱收缩频率增加[22].
　　
　　6抑制骨骼肌细胞凋亡
　　
　　实验证实TNF-α诱导小鼠骨骼肌细胞凋亡与NF-κB的活化相关[23],激活P2Y6受体能降低TNF-a诱导的NF-κB提升作用而间接发挥抑制细胞凋亡的作用[24].进一步研究发现内源性UDP和合成激动剂MRS2693浓度依赖性保护小鼠骨骼肌细胞细胞凋亡，P2Y6阻断剂能阻止这种保护作用[25].
　　
　　7其他
　　
　　另外，激活P2Y6受体能调节磷脂酶D的活性及磷脂酸生成，且阻断磷脂酶D途径后细胞能通过其他途径促进磷脂酸的生成[26]; 用UDP激活P2Y6受体能有效保护小鼠感染水疱性口炎病毒[27];P2Y6受体能调节白细胞对CCL2的反应能力[28]; 激活P2Y6能够刺激胰岛素的分泌[29]; 以巨噬细胞为研究对象，P2Y6相对于其他P2Y嘌呤受体成员，在巨噬细胞中呈高表达，调控多种促炎症因子如单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子-a和炎性蛋白-1a /p等的转录表达，进一步研究表明，P2Y6主要通过MEK1 /2-ERK1 /2MAPK ~ API信号通路从转录水平上调控MCP-1表达，而非P38、c-Jun氨基末端激酶或NF-κB通路[30].
　　
　　8结语
　　
　　综上所述，P2Y6受体的过度激活会引起严重的生理功能障碍和疾病，P2Y6受体参与心血管疾病、神经病变、呼吸系统疾病及胃肠道疾病等的发生。其中，P2Y6受体介导细胞外核苷酸的活动，以参与心血管疾病的发生发展最为重要，体现在促进血管炎症反应、增强血管张力、促进平滑肌细胞的收缩与增殖等方面，因此寻找P2Y6受体阻断剂的研究可能成为未来心血管疾病药物研究领域的一大热点。同时，P2Y6受体广泛调控各种炎症因子的表达及炎症反应，且与其他受体（Cys LT1R和C5a R受体） 协同调节炎症因子的表达[31],为开展抗炎症药物研究提供了新的靶点。此外，激活P2Y6受体能刺激胰岛素的分泌，相应受体的激动剂和拮抗剂具有开发成治疗糖尿病药物的前景。因此，研究P2Y6受体的生物学效应具有重要的理论和应用价值。未来关于P2Y6受体生物学效应的研究应倾向于在明确其生物学效应后，对其生物学效应进行进一步筛选，确证其在某一领域的实用价值。
　　
　　参考文献：
　　[1]Paikin JS,Eikelboom JW,Cairns JA,et al. New antithromboticagents -insights from clinical trials[J]. Nat Rev Cardiol,2010,7（9） :498 - 509.
　　[2]Riegel AK,Faigle M,Zug S,et al. Selective induction of endo-thelial P2Y6 nucleotide receptor promotes vascular inflammation[J]. Blood,2011,117（8） :2548 - 2555.
　　[3]Garcia RA1,Yan M1,Search D1,et al. P2Y6receptor potenti-ates pro-inflammatory responses in macrophages and exhibits dif-ferential roles in atherosclerotic lesion development[J]. PLo SONE,2014,9（10） :e111385.
　　[4]Wang L,Karlsson L,Moses S,et al. P2 receptor expression pro-files in human vascular smooth muscle and endothelial cells[J].J Cardiovasc Pharmacol,2002,40（6） :841 - 853.
　　[5]Bobbert P,Schlüter H,Schultheiss HP,et al. Diadenosinepolyphosphates Ap3A and Ap4A,but not Ap5A or Ap6A induceproliferation of vascular smooth muscle cells[J]. Biochem Phar-macol,2008,75（10） :1966 - 1973.
　　[6]Govindan S,Taylor EJ,Taylor CW. Ca2 +signalling by P2Y re-ceptors in cultured rat aortic smooth muscle cells[J]. Br J Phar-macol,2010,160（8） :1953 - 1962.
　　[7]Nishida M,Sato Y,Uemura A,et al. P2Y6receptor-Galpha 12 /13 signalling in cardiomyocytes triggers pressure overload-inducedcardiac fibrosis[J]. EMBO J,2008,27（23） :3104 - 3115.
　　[8]Koizumi S,Shigemoto-Mogami Y,Nasu-Tada K,et al. UDP act-ing at P2Y6 receptors is a mediator of microglial phagocytosis[J]. Nature,2007,446（7139） :1091 - 1095.
　　[9]Neher JJ,Neniskyte U,Hornik T,et al. Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neuronsby activated microglia in vitro and in vivo[J]. Glia,2014,62（9） :1463 - 1475.
　　[10]Quintas C,Pinho D,Pereira C,et al. Microglia P2Y6 receptorsmediate nitric oxide release and astrocyte apoptosis[J]. J Neu-roinflammation,2014,11:141.
　　[11]Morioka N,Tokuhara M,Harano S,et al. The activation ofP2Y6 receptor in cultured spinal microglia induces the productionof CCL2 through the MAP kinases-NF-κB pathway[J]. Neurop-harmacology,2013,75（2） :116 - 125.
　　[12]Barragán-Iglesias P,Pineda-Farias JB,Cervantes-Durán C,etal. Role of spinal P2Y6 and P2Y11 receptors in neuropathic painin rats:possible involvement of glial cells[J]. Mol Pain,2014,10:29.
　　[13]Syhr KM,Kallenborn-Gerhardt W,Lu R,et al. Lack of effect ofa P2Y6 receptor antagonist on neuropathic pain behavior in mice[J]. Pharmacol Biochem Behav,2014,124:389 - 395.
　　[14]Marcet B,Horckmans M,Libert F,et al. Extracellular nucleo-tides regulate CCL20 release from human primary airway epitheli-al cells,monocytes and monocyte-derived dendritic cells[J]. JCell Physiol,2007,211（3） :716 - 727.
　　[15]Hao Y,Liang JF,Chow AW,et al. P2Y6 receptor-mediatedproinflammatory signaling in human bronchial epithelia[J].PLo S ONE,2014,9（9） :e106235.
　　[16]Ide S,Nishimaki N,Tsukimoto M,et al. Purine receptor P2Y6mediates cellular response to γ-ray-induced DNA damage[J]. JToxicol Sci,2014,39（1） :15 - 23.
　　[17]Schreiber R,Kunzelmann K. Purinergic P2Y6 receptors induceCa2 +and CFTR dependent Cl-secretion in mouse trachea[J].Cell Physiol Biochem,2005,16（13） :99 - 108.
　　[18]Grbic DM,Degagné E,Langlois C,et al. Intestinal inflamma-tion increases the expression of the P2Y6 receptor on epithelialcells and the release of CXC chemokine ligand 8 by UDP[J]. JImmunol,2008,180（4） :2659 - 2668.
　　[19]Nakamura T,Murata T,Hori M,et al. UDP induces intestinalepithelial migration via the P2Y6 receptor[J]. Br J Pharmacol,2013,170（4） :883 - 892.
　　[20]Yu W,Sun X,Robson SC,et al. Extracellular UDP enhancesP2X-mediated bladder smooth muscle contractility via P2Y6 acti-vation of the phospholipase C / inositol trisphosphate pathway[J]. FASEB J,2013,27（5） :1895 - 1903.
　　[21]Carneiro I,Timóteo MA,Silva I,et al. Activation of P2Y6 re-ceptors increases the voiding frequency in anaesthetized rats byreleasing ATP from the bladder urothelium[J]. Br J Pharmacol,2014,171（14） :3404 - 3419.
　　[22]Timóteo MA,Carneiro I,Silva I,et al. ATP released via pannex-in-1 hemichannels mediates bladder overactivity triggered byurothelial P2Y6 receptors[J]. Biochem Pharmacol,2014,87（2） :371 - 379.
　　[23]Stewart CE,Newcomb PV,Holly JM. Multifaceted roles of TNF-alpha in myoblast destruction:a multitude of signal transductionpathways[J]. J Cell Physiol,2004,198（2） :237 - 247.
　　[24]Zheng J,Wang R,Zambraski E,et al. A novel protective actionof adenosine A3 receptors:attenuation of skeletal muscle ische-mia and reperfusion injury[J]. Am J Physiol,2007,293:3685- 3691.
　　[25]Mamedova LK,Wang R,Besada P. Attenuation of apoptosis invitro and ischemia / reperfusion injury in vivo in mouse skeletalmuscle by P2Y6 receptor activation[J]. Pharmacol Res,2008,58（34） :232 - 239.
　　[26]Scott SA,Xiang Y,Mathews TP,et al. Regulation of phospho-lipase D activity and phosphatidic acid production after purinergicP2Y6 receptor stimulation[J]. J Biol Chem,2013,288（28） :20477 - 20487.
　　[27]Li R,Tan B,Yan Y,et al. Extracellular UDP and P2Y6 func-tion as a danger signal to protect mice from vesicular stomatitis vi-rus infection through an increase in IFN-β production[J]. J Im-munol,2014,193（9） :4515 - 4526.
　　[28]Campwala H,Sexton DW,Crossman DC,et al. P2Y6 receptorinhibition perturbs CCL2-evoked signalling in human monocyticand peripheral blood mononuclear cells[J]. J Cell Sci,2014,127（22） :4964 - 4973.
　　[29]Petit P,Lajoix AD,Gross R. P2 purinergic signalling in the pan-creatic beta-cell:control of insulin secretion and pharmacology[J]. Eur J Pharm Sci,2009,37（2） :67 - 75.
　　[30]Zhang Z,Wang Z,Ren H,et al. P2Y6 agonist uridine 5'-diphosphate promotes host defense against bacterial infection viamonocyte chemoattractant protein-1-mediated monocytes / macro-phages recruitment[J]. J Immunol,2011,186（9） :5376 -5387.
　　[31]Jiang Y,Borrelli L,Bacskai BJ,et al. P2Y6 receptors requirean intact cysteinyl leukotriene synthetic and signaling system toinduce survival and activation of mast cells[J]. J Immunol,2009,182（2） :1129 - 1137.