腺苷酸环化酶的研究进展
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摘要
腺苷酸环化酶(adenyl cyclase,AC)是G蛋白偶联受体(G protein-coupled receptor,GPCR)下游的关键信号分子,通过调节环腺苷-3',5'-一磷酸(c AMP)的合成调控多种细胞功能,从而参与机体的多种病理生理过程。哺乳动物细胞表达了9个跨膜AC亚型(AC1～9,mACs)和1个可溶性AC(sAC,也称为AC10),各亚型在不同组织细胞膜微筏(脂筏)中存在差异性表达,由于不同亚型间具有非特异的交叉协同性或拮抗性,各亚型的非选择性激活/抑制会带来很多潜在的不良反应,因此目前还缺乏特异性的激动剂和抑制剂。认识和了解AC各亚型的研究现状,对进一步研究各亚型特异性激动剂/抑制剂及未来靶向药物的研究具有重要意义。
Adenyl cyclase(AC), as a key downstream signaling factor of G protein-coupled receptor(GPCR), is involved in a variety of potential physiological and pathological processes by adjusting the cyclic adenosine-3',5'-monophosphate(cAMP). So far, nine membrane isoforms(AC1–9) and a soluble adenyl cyclase(sAC) have been cloned. They are expressed in different organs, and have different physiological functions. Non-selective activation/inhibition has many potential side effects. In this article we will summarize the current research of AC isoforms. Research on specific agonists/inhibitors and potential targeted drugs is of great significance.
Adenyl cyclase(AC), as a key downstream signaling factor of G protein-coupled receptor(GPCR), is involved in a variety of potential physiological and pathological processes by adjusting the cyclic adenosine-3',5'-monophosphate(cAMP). So far, nine membrane isoforms(AC1–9) and a soluble adenyl cyclase(sAC) have been cloned. They are expressed in different organs, and have different physiological functions. Non-selective activation/inhibition has many potential side effects. In this article we will summarize the current research of AC isoforms. Research on specific agonists/inhibitors and potential targeted drugs is of great significance.
引文
1.Dessauer CW,Watts VJ,Ostrom RS,et al.International Union of Basic and Clinical Pharmacology.CI.Structures and small molecule modulators of mammalian adenylyl cyclases[J].Pharmacol Rev,2017,69(2):93-139.
2.郭艳辉,梁秀银,于双营,等.哺乳动物腺苷酸环化酶的表达调控与功能[J].中国细胞生物学学报,2018,40(3):426-438.GUO Yanhui,LIANG Xiuyin,YU Shuangying,et al.Expression and function of adenylate cyclase in mammals[J].Chinese Journal of Cell Biology,2018,40(3):426-438.
3.黄丽妹,朱建梁,孙敏.哺乳动物腺苷酸环化酶亚型的研究进展[J].临床与病理杂志,2011,31(2):161-166.HUANG Limei,ZHU Jianliang,SUN Min.Advances in the study of adenylate cyclase subtypes in mammals[J].Journal of Clinical and Pathological Research,2011,31(2):161-166.
4.Sadana R,Dessauer CW.Physiological roles for G protein-regulated adenylyl cyclase isoforms:insights from knockout and overexpression studies[J].Neurosignals,2009,17(1):5-22.
5.Aledhni F,Tang T,Madsen K,et al.Stimulation of renin srcretion by catecholamines is dependent on adenylyl cyclases 5 and 6[J].Hypertension,2011,57(3):460-468.
6.Pluznick JL,Zou DJ,Zhang X,et al.functional expression of the olfactory signaling system in the kidney[J].Proc Natl Acad Sci U S A,2009,106(6):2059-2064.
7.Tang T,Lai NC,Wright AT,et al.Adenylyl cyclase 6 deletion increases mortality during sustainedβ-adrenergic receptor stimulation[J].J Mol Cell Cardiol,2013,60:60-67.
8.Wang H,Xu H,Wu LJ,et al.Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain[J].Sci Transl Med,2011,3(65):65ra3.
9.闫佩云.CRTC1-BDNF相关信号通路在阿尔茨海默病早期突触可塑性及认知功能障碍中的机制研究[D].宁波:宁波大学,2017.YAN Peiyun.Mechanism of CRTC1-BDNF related signaling pathway in early synaptic plasticity and cognitive dysfunction in Alzheimer’s disease[D].Ningbo:University of Ningbo,2017.
10.罗本华,张雪竹,赵岚,等.阿尔茨海默病G蛋白-腺苷酸环化酶系统信号途经的机理、防治综述[J].辽宁中医杂志,2012,39(6):1184-1188.LUO Benhua,ZHANG Xuezhu,ZHAO Lan,et al.Mechanism of signal pathway of G protein-adenylate cyclase system in Alzheimer’s disease and its prevention and treatment[J].Liaoning Journal of Traditional Chinese Medicine,2012,39(6):1184-1188.
11.Xiao Z,He L,Takemoto M,et al.Glomerular podocytes express type 1adenylate cyclase:inactivation results in susceptibility to proteinuria[J].Nephron Exp Nephrol,2011,118(3):e39-e48.
12.卓敏.选择性抑制腺苷酸环化酶1的化合物在制备用于治疗神经性疼痛和炎性疼痛的药物中的应用[P].中国专利:CN947717B,2012.ZHUO Min.Selective inhibition of adenylate cyclase 1 in the preparation of drugs for the treatment of neuropathic and inflammatory pain[P].Chinese patent:CN1947717B,2012.
13.Procopio DO,Saba LM,Walter H,et al.Genetic markers of co-morbid depression and alcoholism in women[J].Alcohol Clin Exp Res,2013,37(6):896-904.
14.庞剑月,隋净净,曹素霞,等.5-羟色胺2A受体和腺苷酸环化酶相关基因位点单核苷酸多态性与双相障碍的关联分析[J].中华行为医学与脑科学杂志,2014,23(3):200-202.PANG Jianyue,SUI Jingjing,CAO Suxia,et al.Association analysis of single nucleotide polymorphisms of 5-hydroxytryptamine 2A receptor and adenylate cyclase related gene with biphasic disorder[J].Chinese Journal of Behavioral Medical Science,2014,23(3):200-202.
15.Zachariou V,Liu R,Laplant Q,et al.Distinct roles of adenylyl cyclases1 and 8 in opiate dependence:behavioral,electrophysiological,and molecular studies[J].Biol Psychiatry,2008,63(11):1013-1021.
16.郝江叶,韩绍芳,罗影涛,等.腺苷酸环化酶III(AC3)在非神经细胞内的定位[J].中国细胞生物学学报,2015,37(3):378-386.HAO Jiangye,HAN Shaofang,LUO Yingtao,et al.Localization of adenylate cyclase III(AC3)in non-neuronal cells[J].Chinese Journal of Cell Biology,2015(3):378-386.
17.周艳芬,韩绍芳,舒俐,等.腺苷酸环化酶3缺失对小鼠主要嗅觉表皮组织内相关因子及信号通路的影响[J].中国生物化学与分子生物学报,2016,32(7):816-822.ZHOU Yanfen,HAN Shaofang,SHU Li,et al.Effects of adenylate cyclase 3 deletion on related factors and signaling pathways in the main olfactory epidermis of mice[J].Chinese Journal of Biochemistry and Molecular Biology,2016,32(7):816-822.
18.Wang Z,Storm DR.Maternal behavior is impaired in female mice lacking type 3 adenylyl cyclase[J].Neuropsychopharmacology,2011,36(4):772-781.
19.Seed AM,Kovoor A,Nordman S,et al.Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats:a possible regulatory role in glucose homeostasis[J].Islets,2012,4(5):343-348.
20.陈谢,陈青云,陈莹,等.高脂饮食诱导肥胖大鼠对胰腺组织AC3基因表达的影响[J].广西医科大学学报,2014,31(1):61-63.CHEN Xie,CHEN Qingyun,CHEN Ying,et al.Effects of high fat diet on AC3 gene expression in pancreas of obese rats[J].Journal of Guangxi Medical University,2014,31(1):61-63.
21.Bogard AS.Adenylyl cyclase 2 selectively regulates IL-6 expression in human bronchial smooth muscle cells[D].USA:University of Tennessee Health Science Center,2013.
22.Mühleisen TW,Leber M,Schulze TG,et al.Genome-wide association study reveals two new risk loci for bipolar disorder[J].Nat Commun,2014,5:3339.
23.Li YR,Li J,Zhao SD,et al.Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases[J].Nat Med,2015,21(9):1018-1027.
24.Ho D,Yan L,Iwatsubo K,et al.Modulation ofβ-adrenergic receptor signaling in heart failure and longevity:targeting adenylyl cyclase type5[J].Heart Fail Rev,2010,15(5):495-512.
25.Chen YZ,Matsushita MM,Robertson P,et al.Autosomal dominant familial dyskinesia and facial myokymia:single exome sequencing identifies a mutation in adenylyl cyclase 5[J].Arch Neurol,2012,69(5):630-635.
26.Niesor EJ,Benghozi R,Amouyel P,et al.Adenylyl c yclase 9poly mor phi sms reveal potential link to HDL f unction and cardiovascular events in multiple pathologies:potential implications in sickle cell disease[J].Cardiovasc Drugs Ther,2015,29(6):563-572.
27.Yong SL,Marmorstein LY,Marmorstein AD.Soluble adenylyl cyclase in the eye[J].Biochim Biophys Acta,2014,1842(12):2579-2583.
28.Flacke JP,Flacke H,Appukuttan A,et al.Type 10 soluble adenylyl c yclase is overex pressed in prostate carcinoma and controls proliferation of prostate cancer cells[J].J Biol Chem,2013,288(5):3126-3135.
29.游爱平,王芬,刘岑,等.可溶性腺苷酸环化酶介导的信号通路在精子获能中的研究进展[J].中国妇幼保健,2017,32(4):877-879.YOU Aiping,WANG Fen,LIU Cen,et al.Advances in the study of soluble adenylate cyclase mediated signaling pathway in sperm capacitation[J].Maternal and Child Health Care of China,201732(4):877-879.
30.周翔天,瞿佳,陶奕瑾,等.腺苷酸环化酶抑制剂作为抑制近视药物的应用[P].中国专利:WO2012089053A1,2012-07-05.ZHOU Xiangtian,QU Jia,TAO Yijin,et al.Adenylate cyclase inhibitor as a drug for myopia inhibition[P].Chinese patent:WO 2012089053A1,2012-07-05.
31.Holz GG,Leech CA,Chepurny OG.New insights concerning the molecular basis for defective glucoregulation in soluble adenylyl cyclase knockout mice[J].Biochim Biophys Acta,2014,1842(12 Pt B):2593-2600.
2.郭艳辉,梁秀银,于双营,等.哺乳动物腺苷酸环化酶的表达调控与功能[J].中国细胞生物学学报,2018,40(3):426-438.GUO Yanhui,LIANG Xiuyin,YU Shuangying,et al.Expression and function of adenylate cyclase in mammals[J].Chinese Journal of Cell Biology,2018,40(3):426-438.
3.黄丽妹,朱建梁,孙敏.哺乳动物腺苷酸环化酶亚型的研究进展[J].临床与病理杂志,2011,31(2):161-166.HUANG Limei,ZHU Jianliang,SUN Min.Advances in the study of adenylate cyclase subtypes in mammals[J].Journal of Clinical and Pathological Research,2011,31(2):161-166.
4.Sadana R,Dessauer CW.Physiological roles for G protein-regulated adenylyl cyclase isoforms:insights from knockout and overexpression studies[J].Neurosignals,2009,17(1):5-22.
5.Aledhni F,Tang T,Madsen K,et al.Stimulation of renin srcretion by catecholamines is dependent on adenylyl cyclases 5 and 6[J].Hypertension,2011,57(3):460-468.
6.Pluznick JL,Zou DJ,Zhang X,et al.functional expression of the olfactory signaling system in the kidney[J].Proc Natl Acad Sci U S A,2009,106(6):2059-2064.
7.Tang T,Lai NC,Wright AT,et al.Adenylyl cyclase 6 deletion increases mortality during sustainedβ-adrenergic receptor stimulation[J].J Mol Cell Cardiol,2013,60:60-67.
8.Wang H,Xu H,Wu LJ,et al.Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain[J].Sci Transl Med,2011,3(65):65ra3.
9.闫佩云.CRTC1-BDNF相关信号通路在阿尔茨海默病早期突触可塑性及认知功能障碍中的机制研究[D].宁波:宁波大学,2017.YAN Peiyun.Mechanism of CRTC1-BDNF related signaling pathway in early synaptic plasticity and cognitive dysfunction in Alzheimer’s disease[D].Ningbo:University of Ningbo,2017.
10.罗本华,张雪竹,赵岚,等.阿尔茨海默病G蛋白-腺苷酸环化酶系统信号途经的机理、防治综述[J].辽宁中医杂志,2012,39(6):1184-1188.LUO Benhua,ZHANG Xuezhu,ZHAO Lan,et al.Mechanism of signal pathway of G protein-adenylate cyclase system in Alzheimer’s disease and its prevention and treatment[J].Liaoning Journal of Traditional Chinese Medicine,2012,39(6):1184-1188.
11.Xiao Z,He L,Takemoto M,et al.Glomerular podocytes express type 1adenylate cyclase:inactivation results in susceptibility to proteinuria[J].Nephron Exp Nephrol,2011,118(3):e39-e48.
12.卓敏.选择性抑制腺苷酸环化酶1的化合物在制备用于治疗神经性疼痛和炎性疼痛的药物中的应用[P].中国专利:CN947717B,2012.ZHUO Min.Selective inhibition of adenylate cyclase 1 in the preparation of drugs for the treatment of neuropathic and inflammatory pain[P].Chinese patent:CN1947717B,2012.
13.Procopio DO,Saba LM,Walter H,et al.Genetic markers of co-morbid depression and alcoholism in women[J].Alcohol Clin Exp Res,2013,37(6):896-904.
14.庞剑月,隋净净,曹素霞,等.5-羟色胺2A受体和腺苷酸环化酶相关基因位点单核苷酸多态性与双相障碍的关联分析[J].中华行为医学与脑科学杂志,2014,23(3):200-202.PANG Jianyue,SUI Jingjing,CAO Suxia,et al.Association analysis of single nucleotide polymorphisms of 5-hydroxytryptamine 2A receptor and adenylate cyclase related gene with biphasic disorder[J].Chinese Journal of Behavioral Medical Science,2014,23(3):200-202.
15.Zachariou V,Liu R,Laplant Q,et al.Distinct roles of adenylyl cyclases1 and 8 in opiate dependence:behavioral,electrophysiological,and molecular studies[J].Biol Psychiatry,2008,63(11):1013-1021.
16.郝江叶,韩绍芳,罗影涛,等.腺苷酸环化酶III(AC3)在非神经细胞内的定位[J].中国细胞生物学学报,2015,37(3):378-386.HAO Jiangye,HAN Shaofang,LUO Yingtao,et al.Localization of adenylate cyclase III(AC3)in non-neuronal cells[J].Chinese Journal of Cell Biology,2015(3):378-386.
17.周艳芬,韩绍芳,舒俐,等.腺苷酸环化酶3缺失对小鼠主要嗅觉表皮组织内相关因子及信号通路的影响[J].中国生物化学与分子生物学报,2016,32(7):816-822.ZHOU Yanfen,HAN Shaofang,SHU Li,et al.Effects of adenylate cyclase 3 deletion on related factors and signaling pathways in the main olfactory epidermis of mice[J].Chinese Journal of Biochemistry and Molecular Biology,2016,32(7):816-822.
18.Wang Z,Storm DR.Maternal behavior is impaired in female mice lacking type 3 adenylyl cyclase[J].Neuropsychopharmacology,2011,36(4):772-781.
19.Seed AM,Kovoor A,Nordman S,et al.Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats:a possible regulatory role in glucose homeostasis[J].Islets,2012,4(5):343-348.
20.陈谢,陈青云,陈莹,等.高脂饮食诱导肥胖大鼠对胰腺组织AC3基因表达的影响[J].广西医科大学学报,2014,31(1):61-63.CHEN Xie,CHEN Qingyun,CHEN Ying,et al.Effects of high fat diet on AC3 gene expression in pancreas of obese rats[J].Journal of Guangxi Medical University,2014,31(1):61-63.
21.Bogard AS.Adenylyl cyclase 2 selectively regulates IL-6 expression in human bronchial smooth muscle cells[D].USA:University of Tennessee Health Science Center,2013.
22.Mühleisen TW,Leber M,Schulze TG,et al.Genome-wide association study reveals two new risk loci for bipolar disorder[J].Nat Commun,2014,5:3339.
23.Li YR,Li J,Zhao SD,et al.Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases[J].Nat Med,2015,21(9):1018-1027.
24.Ho D,Yan L,Iwatsubo K,et al.Modulation ofβ-adrenergic receptor signaling in heart failure and longevity:targeting adenylyl cyclase type5[J].Heart Fail Rev,2010,15(5):495-512.
25.Chen YZ,Matsushita MM,Robertson P,et al.Autosomal dominant familial dyskinesia and facial myokymia:single exome sequencing identifies a mutation in adenylyl cyclase 5[J].Arch Neurol,2012,69(5):630-635.
26.Niesor EJ,Benghozi R,Amouyel P,et al.Adenylyl c yclase 9poly mor phi sms reveal potential link to HDL f unction and cardiovascular events in multiple pathologies:potential implications in sickle cell disease[J].Cardiovasc Drugs Ther,2015,29(6):563-572.
27.Yong SL,Marmorstein LY,Marmorstein AD.Soluble adenylyl cyclase in the eye[J].Biochim Biophys Acta,2014,1842(12):2579-2583.
28.Flacke JP,Flacke H,Appukuttan A,et al.Type 10 soluble adenylyl c yclase is overex pressed in prostate carcinoma and controls proliferation of prostate cancer cells[J].J Biol Chem,2013,288(5):3126-3135.
29.游爱平,王芬,刘岑,等.可溶性腺苷酸环化酶介导的信号通路在精子获能中的研究进展[J].中国妇幼保健,2017,32(4):877-879.YOU Aiping,WANG Fen,LIU Cen,et al.Advances in the study of soluble adenylate cyclase mediated signaling pathway in sperm capacitation[J].Maternal and Child Health Care of China,201732(4):877-879.
30.周翔天,瞿佳,陶奕瑾,等.腺苷酸环化酶抑制剂作为抑制近视药物的应用[P].中国专利:WO2012089053A1,2012-07-05.ZHOU Xiangtian,QU Jia,TAO Yijin,et al.Adenylate cyclase inhibitor as a drug for myopia inhibition[P].Chinese patent:WO 2012089053A1,2012-07-05.
31.Holz GG,Leech CA,Chepurny OG.New insights concerning the molecular basis for defective glucoregulation in soluble adenylyl cyclase knockout mice[J].Biochim Biophys Acta,2014,1842(12 Pt B):2593-2600.