Selective interference of β-arrestin 1 with κ and δ but not μ opioid receptor G protein coupling
Selective interference of β-arrestin 1 with κ and δ but not μ opioid receptor G protein coupling
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DOI：
10.1074/jbc.273.38.24328
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发表时间：
1998-09-18
影响因子：
4.8
通讯作者：
Pei, G
中科院分区：
文献类型：
--
作者：
Cheng, ZJ;Yu, QM;Pei, G
在阿片受体和β-arr1共转染人胚胎肾293细胞中，研究了β-arr1在调节Kappa、Delta和Mu阿片受体反应性中的作用。人β-arr1的表达减弱了kappa和Delta阿片受体亚型对cAMP产生的抑制，使kappa激动剂U69593和Delta激动剂[D-Pen(2)，D-Pen(5)]脑啡肽的EC50值增加100倍，最大反应降低30-40%。β-arr1与Mu阿片受体共表达不影响Mu激动剂[D-Ala(2)，N-Me-Phe(4)，Gly(5)-ol]脑啡肽的量效关系。同时，Kappa和Delta受体介导的G蛋白激活也被β-arr1的过度表达显著减弱，而u激动剂刺激的反应保持不变。这些结果表明，β-arr1干扰受体/G蛋白偶联并差异性调节阿片受体的反应性，截断Kappa和Delta阿片受体的羧基末端可取消β-arr1对这两种受体反应性的抑制。此外，Mu阿片受体的羧基末端被Delta受体的相应部分替换后，对β-arr1的调节变得敏感，kappa阿片受体羧基末端潜在的磷酸化位点的去除导致β-arr1对受体介导的反应的影响减弱。这些结果表明，受体羧基末端及其磷酸化在β-arr1与阿片受体的相互作用中起着重要作用。
The role of beta-arrestin 1 (beta-arr1) in regulation of responsiveness of kappa, delta, and mu opioid receptors has been investigated in human embryonic kidney 293 cells cotransfected with opioid receptor and beta-arr1. Expression of human beta-arr1 attenuated kappa and delta opioid receptor subtype-mediated inhibition of cAMP production and resulted in a 100-fold increase of EC50 values for kappa-agonist U69593 and delta-agonist [D-Pen(2),D-Pen(5)]enkephalin and 30-40% reduction of their maximal responses. In contrast, coexpression of beta-arr1 with mu opioid receptor did not affect the concentration-effect relationship of mu-agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin. In parallel, kappa and delta receptor-mediated G protein activation was also remarkably attenuated by overexpression of beta-arr1, while the mu-agonist-stimulated response remained intact. These results indicate that beta-arr1 interferes receptor/G protein coupling and differentially regulates the responsiveness of opioid receptors, Truncation of kappa and delta opioid receptors at carboxyl termini abolished inhibition of beta-arr1 on the responsiveness of both receptors. Furthermore, mu opioid receptor became sensitive to beta-arr1 regulation following replacement of its carboxyl terminus with the corresponding portion of the delta receptor, Removal of potential phosphorylation sites on the carboxyl terminus of kappa opioid receptor led to reduced effect of beta-arr1 on the receptor-mediated response, These results suggest that receptor carboxyl terminus and its phosphorylation play an important role in the interaction of beta-arr1 and opioid receptors.