Oligomerization of opioid receptors with β2-adrenergic receptors:: A role in trafficking and mitogen-activated protein kinase activation
Oligomerization of opioid receptors with β2-adrenergic receptors:: A role in trafficking and mitogen-activated protein kinase activation
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DOI：
10.1073/pnas.011384898
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发表时间：
2001-01-02
影响因子：
11.1
通讯作者：
Devi, LA
中科院分区：
文献类型：
--
作者：
Jordan, BA;Trapaidze, N;Devi, LA
G蛋白偶联受体(GPCRs)最近加入了细胞表面二聚化受体的行列。二聚化作用已被证明可以改变这些受体的配体结合、信号传递和运输特性。最近的研究表明，GPCRs与密切相关的成员发生异源二聚，导致其功能的调节。在这项研究中，我们试图确定连接到不同G蛋白家族的GPCR超家族成员是否可以结合并形成寡聚体，我们选择了与刺激性G蛋白偶联的β(2)肾上腺素能受体和与抑制性G蛋白偶联的Delta和kappa阿片受体。β(2)和Delta受体经历强大的激动剂介导的内吞作用，而kappa受体不经历。我们发现，当共表达时，β(2)受体可以与Delta和Kappa受体形成异构体复合体，这种异源齐聚不会显著改变受体的配体结合或偶联特性。然而，它影响受体的转运特性，例如，我们发现当Delta受体与β(2)受体共表达时，经历异丙肾上腺素介导的内吞作用。相反，这些细胞中的β(2)受体经历埃托啡介导的内吞作用，然而，当与kappa受体共表达时，β(2)受体既不经历阿片或异丙肾上腺素介导的内吞作用。此外，这些细胞表现出异丙肾上腺素诱导的丝裂原激活蛋白激酶的磷酸化显著减少。综上所述，这些结果提供了GPCRs与不同类型的G-蛋白偶联的异构化的直接证据，这导致了受体运输和信号转导的调节。
G-protein-coupled receptors (GPCRs) have recently joined the list of cell surface receptors that dimerize. Dimerization has been shown to alter the ligand-binding, signaling, and trafficking properties of these receptors. Recent studies have shown that GPCRs heterodimerize with closely related members, resulting in the modulation of their function. In this study, we have attempted to determine whether members of GPCR superfamilies that couple to different families of G-proteins can associate and form oligomers, We chose the beta (2) adrenergic receptor that couples to stimulatory G-proteins and delta & kappa opioid receptors that couple to inhibitory G-proteins. beta (2) and delta receptors undergo robust agonist-mediated endocytosis, whereas kappa receptors do not. We find that when coexpressed, beta (2) receptors can form heteromeric complexes with both delta and kappa receptors, This heterooligomerization does not significantly alter the ligand binding or coupling properties of the receptors. However, it affects the trafficking properties of the receptors, For example, we find that delta receptors, when coexpressed with beta (2) receptors, undergo isoproterenol-mediated endocytosis. Conversely, beta (2) receptors in these cells undergo etorphine-mediated endocytosis, However, beta (2) receptors, when coexpressed with kappa receptors, undergo neither opioid- nor isoproterenol-mediated endocytosis. Moreover, these cells exhibit a substantial decrease in the isoproterenol-induced phosphorylation of mitogen-activated protein kinases. Taken together, these results provide direct evidence of heteromerization of GPCRs that couple to different types of G-proteins, which results in the modulation of receptor trafficking and signal transduction.