Tallent M, Dichter M A, Reisine T
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Neuroscience. 1998 Aug;85(3):873-85. doi: 10.1016/s0306-4522(97)00675-1.
To directly compare the regulation of the cloned kappa and mu opioid receptor, we expressed them in the same cells, the mouse anterior pituitary cell line AtT-20. The coupling of an endogenous somatostatin receptor to adenylyl cyclase and an inward rectifier K+ current has been well characterized in these cells, enabling us to do parallel studies comparing the regulation of both the kappa and the mu receptor to this somatostatin receptor. We show that the kappa receptor readily uncoupled from the K+ current and from adenylyl cyclase after a 1 h pretreatment with agonist, as indicated by the loss in the ability of the agonist to induce a functional response. The desensitization of the kappa receptor was homologous, as the ability of somatostatin to mediate inhibition of adenylyl cyclase or potentiation of the K+ current was not altered by kappa receptor desensitization. The mu receptor uncoupled from the K+ current but not adenylyl cyclase after a 1 h pretreatment with agonist. Somatostatin was no longer able to potentiate the K+ current after mu receptor desensitization, thus this desensitization was heterologous. Interestingly, pretreatment with a somatostatin agonist caused uncoupling of the mu receptor but not the kappa receptor from the K+ current. These results show that in the same cell line, after a 1 h pretreatment with agonist, the kappa receptor displays homologous regulation, whereas the mu receptor undergoes only a heterologous form of desensitization. mu receptor desensitization may lead to the alterations of diverse downstream events, whereas kappa receptor regulation apparently occurs at the level of the receptor itself. Broad alterations of non-opioid systems by the mu receptor could be relevant to the addictive properties of mu agonists. Comparison of kappa and mu receptor regulation may help define the properties of the mu receptor which are important in the development of addiction, tolerance, and withdrawal to opioid drugs. These are the first studies to directly compare the coupling of the kappa and mu receptors to two different effectors in the same mammalian expression system.
为了直接比较克隆的κ和μ阿片受体的调节情况，我们将它们在同一细胞系——小鼠垂体前叶细胞系AtT-20中进行表达。内源性生长抑素受体与腺苷酸环化酶及内向整流钾电流的偶联在这些细胞中已有充分的特征描述，这使我们能够进行平行研究，比较κ和μ受体与该生长抑素受体的调节情况。我们发现，在用激动剂预处理1小时后，κ受体很容易从钾电流和腺苷酸环化酶上解偶联，这表现为激动剂诱导功能反应的能力丧失。κ受体的脱敏是同源的，因为生长抑素介导的对腺苷酸环化酶的抑制或对钾电流的增强作用不会因κ受体脱敏而改变。在用激动剂预处理1小时后，μ受体从钾电流上解偶联，但未从腺苷酸环化酶上解偶联。μ受体脱敏后，生长抑素不再能够增强钾电流，因此这种脱敏是异源的。有趣的是，用生长抑素激动剂预处理会导致μ受体而非κ受体从钾电流上解偶联。这些结果表明，在同一细胞系中，用激动剂预处理1小时后，κ受体表现出同源调节，而μ受体仅经历异源形式的脱敏。μ受体脱敏可能导致多种下游事件的改变，而κ受体调节显然发生在受体自身水平。μ受体对非阿片系统的广泛改变可能与μ激动剂的成瘾特性有关。比较κ和μ受体的调节可能有助于确定μ受体在阿片类药物成瘾、耐受性和戒断发展中重要的特性。这些是首次在同一哺乳动物表达系统中直接比较κ和μ受体与两种不同效应器偶联的研究。
