Heterodimerization of ORL1 and Opioid Receptors and Its Consequences for N-type Calcium Channel Regulation
Heterodimerization of ORL1 and Opioid Receptors and Its Consequences for N-type Calcium Channel Regulation
复制标题
DOI：
10.1074/jbc.m109.040634
复制
发表时间：
2010-01-08
影响因子：
4.8
通讯作者：
Zamponi, Gerald W.
中科院分区：
文献类型：
--
作者：
Evans, Rhian M.;You, Haitao;Zamponi, Gerald W.
我们研究了ORL 1受体和阿片受体家族的经典成员的异源二聚化。所有三类阿片受体都可以与来自转染的tsA-201细胞裂解物和大鼠背根神经节裂解物的ORL 1受体共免疫沉淀，表明这些受体可以形成异源二聚体。与这一假设一致，在表达任一阿片受体与ORL 1的细胞中，通过应用痛敏肽延长ORL 1受体活化导致阿片受体内化。相反，μ-，δ-和κ-阿片受体激活与适当的配体触发了ORL 1的内化。μ-阿片受体/ORL 1受体异二聚体显示与N型钙通道相关，μ-阿片受体的激活触发N型通道内化，但仅在ORL 1存在下。此外，阿片受体/ORL 1受体异二聚体的形成减弱了ORL 1受体介导的N型通道抑制，部分原因是组成性阿片受体活性。总的来说，我们的数据支持ORL 1和经典阿片受体之间存在异源二聚体，对效应器如N型钙通道具有深远的意义。
We have investigated the heterodimerization of ORL1 receptors and classical members of the opioid receptor family. All three classes of opioid receptors could be co-immunoprecipitated with ORL1 receptors from both transfected tsA-201 cell lysate and rat dorsal root ganglia lysate, suggesting that these receptors can form heterodimers. Consistent with this hypothesis, in cells expressing either one of the opioid receptors together with ORL1, prolonged ORL1 receptor activation via nociceptin application resulted in internalization of the opioid receptors. Conversely, mu-, delta-, and kappa-opioid receptor activation with the appropriate ligands triggered the internalization of ORL1. The mu-opioid receptor/ORL1 receptor heterodimers were shown to associate with N-type calcium channels, with activation of mu-opioid receptors triggering N-type channel internalization, but only in the presence of ORL1. Furthermore, the formation of opioid receptor/ORL1 receptor heterodimers attenuated the ORL1 receptor-mediated inhibition of N-type channels, in part because of constitutive opioid receptor activity. Collectively, our data support the existence of heterodimers between ORL1 and classical opioid receptors, with profound implications for effectors such as N-type calcium channels.