胍丁胺-I1咪唑啉受体系统对阿片长期处理导致的μ-阿片受体代偿性适应的调节
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摘要
尽管前期的研究工作表明胍丁胺抗阿片依赖与其激活I1咪唑啉受体(I1R)尽而在受体后水平抑制阿片长期处理引起的阿片受体信号转导通路代偿性上调相关，但胍丁胺抗阿片依赖是否还与其激活I1R尽而在受体水平抑制阿片长期处理引起的阿片受体代偿性改变尚不明确。本文旨在研究胍丁胺对阿片长期处理引起的阿片受体代偿性适应的抑制作用，及其可能的作用机制，为认识胍丁胺-I1R作用系统调节阿片功能的分子机制提供新的实验依据。
本研究以共同稳定表达μ-阿片受体(MOR)和I1-咪唑啉受体候选蛋白(IRAS)的CHO细胞(CHO-μ／IRAS)为实验模型，以单纯表达MOR的CHO细胞(CHO-μ)为对照，首先确定了在CHO-μ/IRAS和CHO-μ两个表达体系中，MOR的表达量和对配体的亲和力无显著差异，MOR信号转导通路对激动剂刺激的反应无显著差异。阿片受体激动剂DAMGO([D-Ala2，N-Me-Phe4，Gly5-01]-enkephalin，10μM)处理CHO-μ／IRAS细胞30分钟后MOR出现脱敏，胍丁胺(10nM～100μM)和DAMGO共同处理CHO-μ/IRAS对上述DAMGO处理引起的MOR的脱敏过程无显著影响。DAMGO(1μM)分别处理两株细胞12小时后可出现MOR下调，胍丁胺(1～100nM)和DAMGO共同预处理上述两株细胞12小时，能够浓度依赖性地抑制由DANGO预处理引起的CHO-μ／IRAS细胞中MOR的下调，而相同浓度胍丁胺对CHO-μ细胞中由DAMGO预处理引起的MOR的下调无显著影响。胍丁胺这一作用能被I1R阻断剂依法克生(Efaroxan，Efa)所阻断。DAMGO(1μM)预处理两细胞30分钟后，MOR均发生内吞。胍丁胺(1nM～1μM)和DAMGO共同预处理两细胞30分钟，胍丁胺能浓度依赖性地抑制由DANGO预处理引起的CHO-μ/IRAS细胞中MOR的内吞，而相同浓度胍丁胺对CHO-μ细胞中由DAMGO预处理引起的MOR的内吞无显著影响，且这一作用同样能被依法克生所阻断，提示胍丁胺通过激活I1R对DAMGO预处理引起的MOR内吞具有显著的抑制作用，这可能是胍丁胺-I1R作用系统抑制MOR下调的分子基础。在Western blot实验中发现，用DAMGO(5μM)预处理CHO-μ／IRAS和CHO-μ细胞30分钟后，两细胞系中MOR Ser~(375)磷酸化作用显著增强，提示Ser~(375)磷酸化是影响MOR内吞的重要因素之一，胍丁胺(10nM～1μM)和DAMGO共同预处理CHO-μ／IRAS和CHO-μ细胞30分钟，对两细胞中MOR Ser~(375)磷酸化作用均无显著性影响，提示胍丁胺-I1R作用系统并不是通过抑制MOR Ser~(375)磷酸化作用而抑制MOR内吞。胍丁胺(10nM-1μM)对CHO-μ和CHO-μ／IRAS细胞中MOR mRNA合成无影响。
综上所述，本文通过使用共同稳定表达MOR和I1R的CHO-μ／IRAS细胞，以单独表达MOR的CHO-μ细胞为对照，首次在受体水平提供了胍丁胺通过作用于I1R而抑制阿片依赖的直接实验证据，其分子机制可能主要是胍丁胺激活I1R抑制阿片激动剂诱导的MOR的内吞，进而进一步抑制MOR下调。而胍丁胺-I1R作用系统抑制阿片依赖对MOR的合成无影响，其对MOR内吞的抑制也并不是通过影响MOR Ser~(375)磷酸化作用而实现的。
Previous studies showed agmatine, an endogenous I_1-imidazoline receptor ligand, prevents opioid dependence in the post-acceptor level, which may be related that agmatine acting on I1R inbibits compensatory up-regulation after long-term treatment of opioid. Is agmatine preventing opioid dependence in the acceptor level relate to opioid acceptor compensatory change through activating I1R? There are no reports about this. Present study, therefore, is to directly demonstrate whether agmatine-I1R system participates in the modulation to opioid acceptor compensatory adaptation in the acceptor level after long-term treatment of opioid, and to discuss its molecular mechanism.
Firstly, Two cell lines, Chinese hamster ovary cells expressingμ-opioid receptor alone (CHO-μ) and co-expressingμ-opioid receptor and imidazoline receptor antisera-selected protein (IRAS), a candidate for I1 imidazoline receptor, (CHO-μ/IRAS), were used to show the relationship the opioid function regulation of agmatine and I1R. There was no significant difference of expression of MOR and affinity to ligand as well as the reaction to agonist between normal CHO-μand CHO-μ/IRAS cells. DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, 10μM)treatment for 30 min induced desensitization of MOR in CHO-μ/IRAS cells, while agmatine (10nM～10μM) did not influence DAMGO-induced desensitization ofμ-opioid receptor. Chronic treatment by DAMGO (1μM, 12 h) decreased the expression of MOR in CHO-μand CHO-μ/TRAS cells. Agmatine (1～100nM) concentration-dependently inhibited DAMGO-induced down-regulation of MOR in CHO-μ/IRAS cells, while this effect was not observed in CHO-μcells. Efaroxan, an I1 imidazoline receptor-preferential antagonist, completely reversed the effect of agmatine in CHO-μ/IRAS cell. DAMGO (1μM) treatment for 30 min induced internalization of MOR in both cells. Agmatine (1nM～1μM) concentration-dependently inhibited DAMGO-induced intemalization of MOR in CHO-μ/IRAS cells, while this effect was not observed in CHO-μcells. Efaroxan completely reversed the effect of agmatine in CHO-μ/IRAS cell. The Ser~(375) phosphorylation of MOR was significantly increased after DAMGO (5μM) treatment for 30 min in both cells. This result suggested that the Ser~(375) phosphorylation of MOR is one of the important factor effecting the intemalization of MOR. Agmatine (10nM～1μM ) did not alter the DAMGO-induced Ser~(375) phosphorylation of MOR either in CHO-μor in CHO-μ/IRAS. These result indicated that Agmatine-I1R inhibited the intemalization of MOR was not by inhibiting the Ser~(375) phosphorylation of MOR. Meanwhile, Agmatine (10 nM～1μM) did not influence the expression of MOR mRNA in CHO-μ/IRAS cell.
In conclusion, the model system of co-expressing MOR and I1R in CHO cells is used for the first time. Present researches provide the first direct evidence for the participation of I1R in the inhibitory effects of agmatine on opioid tolerance and dependence in the receptor level. Its mechanism may be related that agmatine acting on I1R inhibits intemalization of MOR, and then inhibits its downregulation. Agmatine-I1R system has no influence on the expression of MOR and phosphorylation of Ser~(375) in the process of inhibiting opioid tolerance and dependence.
本研究以共同稳定表达μ-阿片受体(MOR)和I1-咪唑啉受体候选蛋白(IRAS)的CHO细胞(CHO-μ／IRAS)为实验模型，以单纯表达MOR的CHO细胞(CHO-μ)为对照，首先确定了在CHO-μ/IRAS和CHO-μ两个表达体系中，MOR的表达量和对配体的亲和力无显著差异，MOR信号转导通路对激动剂刺激的反应无显著差异。阿片受体激动剂DAMGO([D-Ala2，N-Me-Phe4，Gly5-01]-enkephalin，10μM)处理CHO-μ／IRAS细胞30分钟后MOR出现脱敏，胍丁胺(10nM～100μM)和DAMGO共同处理CHO-μ/IRAS对上述DAMGO处理引起的MOR的脱敏过程无显著影响。DAMGO(1μM)分别处理两株细胞12小时后可出现MOR下调，胍丁胺(1～100nM)和DAMGO共同预处理上述两株细胞12小时，能够浓度依赖性地抑制由DANGO预处理引起的CHO-μ／IRAS细胞中MOR的下调，而相同浓度胍丁胺对CHO-μ细胞中由DAMGO预处理引起的MOR的下调无显著影响。胍丁胺这一作用能被I1R阻断剂依法克生(Efaroxan，Efa)所阻断。DAMGO(1μM)预处理两细胞30分钟后，MOR均发生内吞。胍丁胺(1nM～1μM)和DAMGO共同预处理两细胞30分钟，胍丁胺能浓度依赖性地抑制由DANGO预处理引起的CHO-μ/IRAS细胞中MOR的内吞，而相同浓度胍丁胺对CHO-μ细胞中由DAMGO预处理引起的MOR的内吞无显著影响，且这一作用同样能被依法克生所阻断，提示胍丁胺通过激活I1R对DAMGO预处理引起的MOR内吞具有显著的抑制作用，这可能是胍丁胺-I1R作用系统抑制MOR下调的分子基础。在Western blot实验中发现，用DAMGO(5μM)预处理CHO-μ／IRAS和CHO-μ细胞30分钟后，两细胞系中MOR Ser~(375)磷酸化作用显著增强，提示Ser~(375)磷酸化是影响MOR内吞的重要因素之一，胍丁胺(10nM～1μM)和DAMGO共同预处理CHO-μ／IRAS和CHO-μ细胞30分钟，对两细胞中MOR Ser~(375)磷酸化作用均无显著性影响，提示胍丁胺-I1R作用系统并不是通过抑制MOR Ser~(375)磷酸化作用而抑制MOR内吞。胍丁胺(10nM-1μM)对CHO-μ和CHO-μ／IRAS细胞中MOR mRNA合成无影响。
综上所述，本文通过使用共同稳定表达MOR和I1R的CHO-μ／IRAS细胞，以单独表达MOR的CHO-μ细胞为对照，首次在受体水平提供了胍丁胺通过作用于I1R而抑制阿片依赖的直接实验证据，其分子机制可能主要是胍丁胺激活I1R抑制阿片激动剂诱导的MOR的内吞，进而进一步抑制MOR下调。而胍丁胺-I1R作用系统抑制阿片依赖对MOR的合成无影响，其对MOR内吞的抑制也并不是通过影响MOR Ser~(375)磷酸化作用而实现的。
Previous studies showed agmatine, an endogenous I_1-imidazoline receptor ligand, prevents opioid dependence in the post-acceptor level, which may be related that agmatine acting on I1R inbibits compensatory up-regulation after long-term treatment of opioid. Is agmatine preventing opioid dependence in the acceptor level relate to opioid acceptor compensatory change through activating I1R? There are no reports about this. Present study, therefore, is to directly demonstrate whether agmatine-I1R system participates in the modulation to opioid acceptor compensatory adaptation in the acceptor level after long-term treatment of opioid, and to discuss its molecular mechanism.
Firstly, Two cell lines, Chinese hamster ovary cells expressingμ-opioid receptor alone (CHO-μ) and co-expressingμ-opioid receptor and imidazoline receptor antisera-selected protein (IRAS), a candidate for I1 imidazoline receptor, (CHO-μ/IRAS), were used to show the relationship the opioid function regulation of agmatine and I1R. There was no significant difference of expression of MOR and affinity to ligand as well as the reaction to agonist between normal CHO-μand CHO-μ/IRAS cells. DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, 10μM)treatment for 30 min induced desensitization of MOR in CHO-μ/IRAS cells, while agmatine (10nM～10μM) did not influence DAMGO-induced desensitization ofμ-opioid receptor. Chronic treatment by DAMGO (1μM, 12 h) decreased the expression of MOR in CHO-μand CHO-μ/TRAS cells. Agmatine (1～100nM) concentration-dependently inhibited DAMGO-induced down-regulation of MOR in CHO-μ/IRAS cells, while this effect was not observed in CHO-μcells. Efaroxan, an I1 imidazoline receptor-preferential antagonist, completely reversed the effect of agmatine in CHO-μ/IRAS cell. DAMGO (1μM) treatment for 30 min induced internalization of MOR in both cells. Agmatine (1nM～1μM) concentration-dependently inhibited DAMGO-induced intemalization of MOR in CHO-μ/IRAS cells, while this effect was not observed in CHO-μcells. Efaroxan completely reversed the effect of agmatine in CHO-μ/IRAS cell. The Ser~(375) phosphorylation of MOR was significantly increased after DAMGO (5μM) treatment for 30 min in both cells. This result suggested that the Ser~(375) phosphorylation of MOR is one of the important factor effecting the intemalization of MOR. Agmatine (10nM～1μM ) did not alter the DAMGO-induced Ser~(375) phosphorylation of MOR either in CHO-μor in CHO-μ/IRAS. These result indicated that Agmatine-I1R inhibited the intemalization of MOR was not by inhibiting the Ser~(375) phosphorylation of MOR. Meanwhile, Agmatine (10 nM～1μM) did not influence the expression of MOR mRNA in CHO-μ/IRAS cell.
In conclusion, the model system of co-expressing MOR and I1R in CHO cells is used for the first time. Present researches provide the first direct evidence for the participation of I1R in the inhibitory effects of agmatine on opioid tolerance and dependence in the receptor level. Its mechanism may be related that agmatine acting on I1R inhibits intemalization of MOR, and then inhibits its downregulation. Agmatine-I1R system has no influence on the expression of MOR and phosphorylation of Ser~(375) in the process of inhibiting opioid tolerance and dependence.
引文
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63 Suzuki S, Chuang LF, Doi RH, et al. Kappa-opioid receptors on lymphocytes of a human lymphocytic cell line: Morphine-induced up- regulation as evidenced by competitive RT-PCR and indirect immunofluorescence. Int Immunopharmacol, 2001, 1(9-10): 1733-1742.
64 Narita M, Suzuki M, Narita M, et al. μ-Opioid receptor internalization-dependent and -independent mechanisms of the development of tolerance to μ-opioid receptor agonists: Comparison between etorphine and morphine.Neuroscience, 2006, 138(2):609-619.
65 Zaki PA, Keith DE Jr, Brine GA, et al. Ligand-induced changes in surface mu-opioid receptor number: relationship to G protein activation? J Pharmacol Exp Ther, 2000, 292(3): 1127-1134.
66 Ronnekleiv OK, Bosch MA, Cunningham MJ, et al. Downregulation of mu-opioid receptor mRNA in the mediobasal hypothalamus of the female guinea pig following morphine treatment. Neurosci Let, 1996, 216(2):129-132.
67 Patrck GA, Dewey WL, Huger FP. Disposition of Morphine in chronically infused rats: relationship to antinociception and tolerance. J Pharmacol Exp Ther, 1978, 205:556-562.
68 Zhang X, Wang F, Chen X, et al. Beta-arrestin1 and beta-arrestin2 are differentially required for phosphorylation-dependent and -independent internalization of delta-opioid receptors. J Neurochem, 2005, 95(1):169-178.
69 Qiu Y, Law PY, Loh HH. Mu-opioid receptor desensitization: role of receptor phosphorylation, internalization, and representation. J Biol Chem, 2003, 278:36733-36739.
1 Mark Connor, Peregrine B. Osborne, et al. μ-Opioid receptor desensitization: Is morphine different [J]? Br J Pharmaeo 2004, 143: 685-696
2 Lodowski DT, Tesmer VM, Benovic JL, et al. The structure of G protein-coupled receptor kinase 6 defines a second lineage of GRKS [J]. J Biol Chem 2006, 281: 16785-16793
3 Jiali Li, Bin Xiang, Wenjuan Su, et al. Agonist-induced Formation of Opioid Receptor-G Protein-coupled Receptor Kinase (GRK)-Gβγ Complex on Membrane Is Required for GRK2 Function in Vivo [J]. JBio Chem 2003, 278: 30219-30226
4 M. Ferrer-Alcon, et al. Decreased immunodensities of μ-opioid receptors, receptor kinases GRK2/6 and β-arrestin-2 in postmortem brains of opiate addicts [J]. Mol Brain Res 2004, 121: 114-122
5 Narita M, Suzuki M, Narita M, et al. Mu-opioid receptor internalization-dependent and-independent mechanisms of the development of tolerance to mu-opioid receptor agonists: comparison between etorphine and morphine [J]. Neurosci 2006, 138 (2): 609-619
6 Liu K, JS An. Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence [J]. Brain Res Rev 2001, 38: 1-19
7 Johnson EA. Agonist-selective mechanisms of {micro}-opioid receptor (MOR) desensitization in HEK293 cells [J]. Mol Pharmacol 2006, 70(2): 676-685
8 T. Me'taye', et al. Pathophysiological roles of G-protein-coupled receptor kinases[J]. Cell Signalling 2005, 17: 917-928.
9 McLaughlin JP, Myers LC, Zarek PE, et al. Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance [J]. J Biol Chem. 2004, 16; 279: 1810-1818.
10 Terman GW. G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal [J]. Br J Pharmacol 2004, 141 (1): 55-64
11 Gurevich VV, Gurevich EV. The molecular acrobatics of arrestin activation [J]. Sci 2004, 25: 105-111
12 Bohn LM, Dykstra LA, Lefkowitz RJ, et al. Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery [J]. Mol Pharmacol 2004,66:106-112
13 Bushell T, Endoh T, Simen AA, et al. Molecular components of tolerance to opiates in single hippocampal neurons [J]. Mol. Pharmacol 2002, 6:55-64
14 Celver J, Xu M, Jin W, et al. Distinct domains on the μ-opioid receptor control uncoupling and internalization [J]. Mol Pharmacol 2004,65: 528-537
15 Borgland SL, Connor M, Osborne PB, et al. Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of mu-opioid receptors [J]. J Biol Chem 2003,278:18776-18784
16 Bushell T, Endoh T, Simen AA, et al. Molecular components of tolerance to opiates in single hippocampal neurons [J]. Mol Pharmacol 2002, 61:55—64
17 Bohn LM, Gainetdinov RR, Lin FT, et al. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence [J]. Nature 2000, 408(6813):720-723
18 XL Fan, JS Zhang, XQ Zhang, et al. Differential regulation of β-arrestinl and β-arrestin2 gene expression in rat brain by morphine [J]. Neurosci 2003,117 :383—389
19 Zuo Z. The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance [J]. AnesthAnalg 2005, 101(3):728-734
20 Zhang X, Wang F, Chen X, et al. Beta-arrestin1 and beta-arrestin2 are differentially required for phosphorylation-dependent and -independent internalization of delta-opioid receptors [J]. J Neurochem 2005 ,95(1):169-178
21 Qiu Y, Law PY, Loh HH. Mu-opioid receptor desensitization: role of receptor phosphorylation, internalization, and representation [J]. J Biol Chem 2003, 278:36733-36739
22 Kang J, Shi Y, Xiang B, et al. A nuclear function of beta-arrestin 1 in GPCR signaling: regulation of histone acetylation and gene transcription [J]. Cell 2005 , 123(5):833-847
23 Oakley RH, Laporte SA, Holt JA, et al. Differential affinities of visual arrestin, beta arrestinl, and beta-arrestin2 for G protein-coupled receptors delineate two major classes of receptors [J]. J Biol Chem 2000, 275: 17201-17210
24 Scott MG, Le Rouzic E, Perianin A. et al. Differentia] nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2 [J]. J Biol Chem 2002, 277:37693-37701
25 Wang P, Gao H, Ni Y, et al. Beta-arrestin 2 functions as a G-protein-coupled receptoractivated regulator of oncoprotein Mdm2 [J]. J Biol Chem 2003, 278:6363-6370
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6 Qiu Y, Law PY, Loh HH. Mu-opioid receptor desensitization: role of receptor phosphorylation, internalization, and representation. J Biol Chem, 2003, 278: 36733-36739.
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57 Zhang Q, Purohit V, Yoburn BC. Continuous opioid agonist treatment dose-dependently regulates mu-opioid receptors and dynamin-2 in mouse spinal cord. Synapse, 2005, 56(3): 123-128.
58 Zhang X, Wang F, Chen X, et al. Beta-arrestinl and beta-arrestin2 are differentially required for phosphorylation- dependent and -independent internalization of delta-opioid receptors. J Neurochem, 2005, 95(1): 169-178.
59 Johnson EA, Oldfield S, Braksator E, et al. Agonist-selective mechanisms of mu-opioid receptor desensitization in human embryonic kidney 293 cells. Mol Pharmacol, 2006, 70(2): 676-685.
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61 李伟彦，徐建国，管忍．急、慢性吗啡依赖对大鼠脑组织MOR的调节差异．中华麻醉学杂志，2002，22(3)：158-160．
62 刘惠芬，谢小虎，周文华等．吗啡依赖大鼠脊髓和脑干μ受体和κ受体mRNA表达的研究．中国临床药理学与治疗学，2000，5(1)：1-5．
63 Suzuki S, Chuang LF, Doi RH, et al. Kappa-opioid receptors on lymphocytes of a human lymphocytic cell line: Morphine-induced up- regulation as evidenced by competitive RT-PCR and indirect immunofluorescence. Int Immunopharmacol, 2001, 1(9-10): 1733-1742.
64 Narita M, Suzuki M, Narita M, et al. μ-Opioid receptor internalization-dependent and -independent mechanisms of the development of tolerance to μ-opioid receptor agonists: Comparison between etorphine and morphine.Neuroscience, 2006, 138(2):609-619.
65 Zaki PA, Keith DE Jr, Brine GA, et al. Ligand-induced changes in surface mu-opioid receptor number: relationship to G protein activation? J Pharmacol Exp Ther, 2000, 292(3): 1127-1134.
66 Ronnekleiv OK, Bosch MA, Cunningham MJ, et al. Downregulation of mu-opioid receptor mRNA in the mediobasal hypothalamus of the female guinea pig following morphine treatment. Neurosci Let, 1996, 216(2):129-132.
67 Patrck GA, Dewey WL, Huger FP. Disposition of Morphine in chronically infused rats: relationship to antinociception and tolerance. J Pharmacol Exp Ther, 1978, 205:556-562.
68 Zhang X, Wang F, Chen X, et al. Beta-arrestin1 and beta-arrestin2 are differentially required for phosphorylation-dependent and -independent internalization of delta-opioid receptors. J Neurochem, 2005, 95(1):169-178.
69 Qiu Y, Law PY, Loh HH. Mu-opioid receptor desensitization: role of receptor phosphorylation, internalization, and representation. J Biol Chem, 2003, 278:36733-36739.
1 Mark Connor, Peregrine B. Osborne, et al. μ-Opioid receptor desensitization: Is morphine different [J]? Br J Pharmaeo 2004, 143: 685-696
2 Lodowski DT, Tesmer VM, Benovic JL, et al. The structure of G protein-coupled receptor kinase 6 defines a second lineage of GRKS [J]. J Biol Chem 2006, 281: 16785-16793
3 Jiali Li, Bin Xiang, Wenjuan Su, et al. Agonist-induced Formation of Opioid Receptor-G Protein-coupled Receptor Kinase (GRK)-Gβγ Complex on Membrane Is Required for GRK2 Function in Vivo [J]. JBio Chem 2003, 278: 30219-30226
4 M. Ferrer-Alcon, et al. Decreased immunodensities of μ-opioid receptors, receptor kinases GRK2/6 and β-arrestin-2 in postmortem brains of opiate addicts [J]. Mol Brain Res 2004, 121: 114-122
5 Narita M, Suzuki M, Narita M, et al. Mu-opioid receptor internalization-dependent and-independent mechanisms of the development of tolerance to mu-opioid receptor agonists: comparison between etorphine and morphine [J]. Neurosci 2006, 138 (2): 609-619
6 Liu K, JS An. Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence [J]. Brain Res Rev 2001, 38: 1-19
7 Johnson EA. Agonist-selective mechanisms of {micro}-opioid receptor (MOR) desensitization in HEK293 cells [J]. Mol Pharmacol 2006, 70(2): 676-685
8 T. Me'taye', et al. Pathophysiological roles of G-protein-coupled receptor kinases[J]. Cell Signalling 2005, 17: 917-928.
9 McLaughlin JP, Myers LC, Zarek PE, et al. Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance [J]. J Biol Chem. 2004, 16; 279: 1810-1818.
10 Terman GW. G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal [J]. Br J Pharmacol 2004, 141 (1): 55-64
11 Gurevich VV, Gurevich EV. The molecular acrobatics of arrestin activation [J]. Sci 2004, 25: 105-111
12 Bohn LM, Dykstra LA, Lefkowitz RJ, et al. Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery [J]. Mol Pharmacol 2004,66:106-112
13 Bushell T, Endoh T, Simen AA, et al. Molecular components of tolerance to opiates in single hippocampal neurons [J]. Mol. Pharmacol 2002, 6:55-64
14 Celver J, Xu M, Jin W, et al. Distinct domains on the μ-opioid receptor control uncoupling and internalization [J]. Mol Pharmacol 2004,65: 528-537
15 Borgland SL, Connor M, Osborne PB, et al. Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of mu-opioid receptors [J]. J Biol Chem 2003,278:18776-18784
16 Bushell T, Endoh T, Simen AA, et al. Molecular components of tolerance to opiates in single hippocampal neurons [J]. Mol Pharmacol 2002, 61:55—64
17 Bohn LM, Gainetdinov RR, Lin FT, et al. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence [J]. Nature 2000, 408(6813):720-723
18 XL Fan, JS Zhang, XQ Zhang, et al. Differential regulation of β-arrestinl and β-arrestin2 gene expression in rat brain by morphine [J]. Neurosci 2003,117 :383—389
19 Zuo Z. The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance [J]. AnesthAnalg 2005, 101(3):728-734
20 Zhang X, Wang F, Chen X, et al. Beta-arrestin1 and beta-arrestin2 are differentially required for phosphorylation-dependent and -independent internalization of delta-opioid receptors [J]. J Neurochem 2005 ,95(1):169-178
21 Qiu Y, Law PY, Loh HH. Mu-opioid receptor desensitization: role of receptor phosphorylation, internalization, and representation [J]. J Biol Chem 2003, 278:36733-36739
22 Kang J, Shi Y, Xiang B, et al. A nuclear function of beta-arrestin 1 in GPCR signaling: regulation of histone acetylation and gene transcription [J]. Cell 2005 , 123(5):833-847
23 Oakley RH, Laporte SA, Holt JA, et al. Differential affinities of visual arrestin, beta arrestinl, and beta-arrestin2 for G protein-coupled receptors delineate two major classes of receptors [J]. J Biol Chem 2000, 275: 17201-17210
24 Scott MG, Le Rouzic E, Perianin A. et al. Differentia] nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2 [J]. J Biol Chem 2002, 277:37693-37701
25 Wang P, Gao H, Ni Y, et al. Beta-arrestin 2 functions as a G-protein-coupled receptoractivated regulator of oncoprotein Mdm2 [J]. J Biol Chem 2003, 278:6363-6370