嘌呤受体P2Y在免疫炎症中的功能研究进展
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摘要
P2Y受体(P2YRs)是一类由胞外核苷酸活化的G蛋白偶联受体(GPCRs),从属于嘌呤受体家族。P2Y受体的生理激动剂包括三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、三磷酸尿苷(UTP)、二磷酸尿苷(UDP),核苷酸糖和二核苷酸等。P2Y受体在机体组织内广泛表达,在免疫应答中发挥着重要作用。近年来随着研究深入,P2Y受体在炎症、癌症、心血管和神经退行性疾病中显示出作为药物靶标的巨大潜力,P2Y受体的研究对新药的进一步开发有着重要的意义。本文就P2Y受体的分类、结构,药理学特性及以P2Y受体为靶点的潜在药物等作一综述。
P2 Y receptor(P2 YRs) is a kind of G protein coupled receptor(GPCRs) activated by extracellular nucleotides,belonging to purine receptor family.The physiological activators of P2 Y receptors include dinucleotide or triphosphate nucleotide purine and pyrimidine,such as ATP,ADP,UTP,UDP,nucleotide sugar and dinucleotide.P2 Y receptor is widely expressed in tissue and plays an important role in immune response.In recent years,P2 Y receptor has shown great potential as a drug target in inflammation,cancer,cardiovascular and neurodegenerative diseases,and the study of P2 Y receptor is of great significance for the further development of new drugs.In this paper,the classification,structure,pharmacological properties of P2 Y receptor and potential drugs targeted at P2 Y receptor are reviewed.
P2 Y receptor(P2 YRs) is a kind of G protein coupled receptor(GPCRs) activated by extracellular nucleotides,belonging to purine receptor family.The physiological activators of P2 Y receptors include dinucleotide or triphosphate nucleotide purine and pyrimidine,such as ATP,ADP,UTP,UDP,nucleotide sugar and dinucleotide.P2 Y receptor is widely expressed in tissue and plays an important role in immune response.In recent years,P2 Y receptor has shown great potential as a drug target in inflammation,cancer,cardiovascular and neurodegenerative diseases,and the study of P2 Y receptor is of great significance for the further development of new drugs.In this paper,the classification,structure,pharmacological properties of P2 Y receptor and potential drugs targeted at P2 Y receptor are reviewed.
引文
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[23] KORNUM B R,MINAE K,JULIETTE F,et al.Common variants in P2RY11 are associated with narcolepsy[J].Nature Genetics,2011,43(1):66-71.
[24] BURNSTOCK G.Blood cells:an historical account of the roles of purinergic signalling[J].Purinergic Signal,2015,11(4):411-434.
[25] JUNGER W G.Immune cell regulation by autocrine purinergic signalling[J].Nat Rev Immunol,2011,11(3):201-212.
[26] 曾勇,文爱珍,王顺民,等.P2Y6受体生物学效应的研究进展[J].中国实验动物学报,2016,24(1):107-110.
[27] JIANG Y,BORRELLI L,BACSKAI B J,et al.P2Y6 receptors require an intact cysteinyl leukotriene synthetic and signaling system to induce survival and activation of mast cells[J].J Immunol,2009,182(2):1129-1137.
[28] KAEBISCH C,SCHIPPER D,BABCZYK P,et al.The role of purinergic receptors in stem cell differentiation[J].Comput Struct Biotechnol J,2015(13):75-84.
[29] CICIARELLO M,ZINI R,ROSSI L,et al.Extracellular purines promote the differentiation of human bone marrow-derived mesenchymal stem cells to the osteogenic and adipogenic lineages[J].Stem Cells Deve,2013,22(7):1097-1111.
[30] SMITH J A,ALBEITZ J,BEGLEY C,et al.The epidemiology of dry eye disease:report of the epidemiology subcommittee of the International Dry Eye Work Shop(2007)[J].Ocul Surf,2007,5(2):93-107.
[31] KOHLHAUER M,BERDEAUX A,GHALEH B,et al.Inflammation in atherosclerosis[J].J Assoc Physicians India,2002,48(2):265-266.
[32] BLOM D,YAMIN T,CHAMPY M F.Altered lipoprotein metabolism in P2Y(13) knockout mice[J].Biochim Biophys Acta,2010,1801(12):1349-1360.
[33] AMISTEN S,MEIDUTEABARAVICIENE S,TAN C,et al.ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice[J].Diabetologia,2010,53(9):1927-1934.
[34] TAN C,SALEHI A,SVENSSON S,et al.ADP receptor P2Y(13) induce apoptosis in pancreatic beta-cells[J].Cell Mol Life Sci,2010,67(3):445-453.
[2] ABBRACCHIO M P,BURNSTOCK G.Purinoceptors:are there families of P2X and P2Y purinoceptors?[J].Pharmacol Ther,1994,64(3):445-475.
[3] KASBOHM E A,GUO R,YOWELL C W,et al.Androgen receptor activation by G(s) signaling in prostate cancer cells[J].J Biol Chem,2005,280(12):11583-11589.
[4] LIAO Z,SEYE C I,WEISMAN G A,et al.The P2Y2 nucleotide receptor requires interaction with αv integrins to access and activate G12[J].J Cell Sci,2007,120(Pt 9):1654.
[5] NISHIDA M,SATO Y,UEMURA A,et al.P2Y6 receptor-Gα12/13 signalling in cardiomyocytes triggers pressure overload‐induced cardiac fibrosis[J].EMBO J,2014,27(23):3104-3115.
[6] SKRABANEK L,MURCIA M,BOUVIER M,et al.Requirements and ontology for a G protein-coupled receptor oligomerization knowledge base[J].Bmc Bioinformatics,2007,8(1):177.
[7] KAWASHITA E,TSUJI D,KANNO Y,et al.Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice[J].Jimd Rep,2015(28):85-93.
[8] ECKE D,HANCK T,TULAPURKAR M E,et al.Hetero-oligomerization of the P2Y11 receptor with the P2Y1 receptor controls the internalization and ligand selectivity of the P2Y11 receptor[J].Biochem J,2008,409(1):107-116.
[9] RIBEIRO-FILHO A C,BURI M V,BARROS C C,et al.Functional and molecular evidence for heteromeric association of P2Y 1,receptor with P2Y2,and P2Y4,receptors in mouse granulocytes[J].BMC Pharmacol Toxicol,2016,17(1):29.
[10] ZHONG X,KRIZ R,SEEHRA J,et al.N-linked glycosylation of platelet P2Y12 ADP receptor is essential for signal transduction but not for ligand binding or cell surface expression[J].Febs Letters,2004,562(1-3):111-117.
[11] ALGAIER I,JAKUBOWSKI J A,ASAI F,et al.Interaction of the active metabolite of prasugrel,R‐138727,with cysteine97 and cysteine175 of the human P2Y12 receptor[J].J Thromb Haemost,2010,6(11):1908-1914.
[12] DING Z,KIM S,DORSAM R T,et al.Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues,Cys17 and Cys270[J].Blood,2003,101(10):3908-3914.
[13] JIANG Q,GUO D,LEE B X,et al.A mutational analysis of residues essential for ligand recognition at the human P2Y1 receptor[J].Mol Pharmacol,1997,52(3):499-507.
[14] ERB L,GARRAD R,WANG Y,et al.Site-directed mutagenesis of P2U purinoceptors.Positively charged amino acids in transmembrane helices 6 and 7 affect agonist potency and specificity[J].J Biol Chem,1995,270(9):4185-4188.
[15] HOFFMANN K,BAQI Y,MORENA M S,et al.Interaction of new,very potent non-nucleotide antagonists with Arg256 of the human platelet P2Y12 receptor[J].J Pharmacol Exp Ther,2009,331(2):648-655.
[16] BAGCHI S,LIAO Z,GONZALEZ F N,et al.The P2Y2 Nucleotide Receptor Interacts with αv Integrins to Activate Go and Induce Cell Migration[J].J Biol Chem,2005,280(47):39050-39057.
[17] HEROLD C L,QI A D,HARDEN T K,et al.Agonist Versus Antagonist Action of ATP at the P2Y4 Receptor Is Determined by the Second Extracellular Loop[J].J Biol Chem,2004,279(12):11456-11464.
[18] CATTANEO M,ZIGHETTI M L,LOMBARDI R,et al.Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding[J].Proc Natl Acad Sci U S A,2003,100(4):1978-1983.
[19] DALY M E,DAWOOD B B,LESTER W A,et al.Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study[J].Blood,2009,113(17):4110-4113.
[20] ELLIOTT M R,CHEKENI F B,TRAMPONT P C,et al.Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance[J].Nature,2009,461(7261):282-286.
[21] JUNGER W G.Immune cell regulation by autocrine purinergic signalling[J].Nat Rev Immunol,2011,11(3):201-212.
[22] IFUKU M,BUONFIGLIOLI A,JORDAN P,et al.TLR2 controls random motility,while TLR7 regulates chemotaxis of microglial cells via distinct pathways[J].Brain Behav Immun,2016(58):338-347.
[23] KORNUM B R,MINAE K,JULIETTE F,et al.Common variants in P2RY11 are associated with narcolepsy[J].Nature Genetics,2011,43(1):66-71.
[24] BURNSTOCK G.Blood cells:an historical account of the roles of purinergic signalling[J].Purinergic Signal,2015,11(4):411-434.
[25] JUNGER W G.Immune cell regulation by autocrine purinergic signalling[J].Nat Rev Immunol,2011,11(3):201-212.
[26] 曾勇,文爱珍,王顺民,等.P2Y6受体生物学效应的研究进展[J].中国实验动物学报,2016,24(1):107-110.
[27] JIANG Y,BORRELLI L,BACSKAI B J,et al.P2Y6 receptors require an intact cysteinyl leukotriene synthetic and signaling system to induce survival and activation of mast cells[J].J Immunol,2009,182(2):1129-1137.
[28] KAEBISCH C,SCHIPPER D,BABCZYK P,et al.The role of purinergic receptors in stem cell differentiation[J].Comput Struct Biotechnol J,2015(13):75-84.
[29] CICIARELLO M,ZINI R,ROSSI L,et al.Extracellular purines promote the differentiation of human bone marrow-derived mesenchymal stem cells to the osteogenic and adipogenic lineages[J].Stem Cells Deve,2013,22(7):1097-1111.
[30] SMITH J A,ALBEITZ J,BEGLEY C,et al.The epidemiology of dry eye disease:report of the epidemiology subcommittee of the International Dry Eye Work Shop(2007)[J].Ocul Surf,2007,5(2):93-107.
[31] KOHLHAUER M,BERDEAUX A,GHALEH B,et al.Inflammation in atherosclerosis[J].J Assoc Physicians India,2002,48(2):265-266.
[32] BLOM D,YAMIN T,CHAMPY M F.Altered lipoprotein metabolism in P2Y(13) knockout mice[J].Biochim Biophys Acta,2010,1801(12):1349-1360.
[33] AMISTEN S,MEIDUTEABARAVICIENE S,TAN C,et al.ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice[J].Diabetologia,2010,53(9):1927-1934.
[34] TAN C,SALEHI A,SVENSSON S,et al.ADP receptor P2Y(13) induce apoptosis in pancreatic beta-cells[J].Cell Mol Life Sci,2010,67(3):445-453.