G-protein-coupled receptor heterodimerization modulates receptor function
G-protein-coupled receptor heterodimerization modulates receptor function
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作者：
Jordan, BA;Devi, LA
阿片类药物系统调节多种生理过程，包括镇痛、应激反应、免疫反应和神经内分泌功能(1)。药理学和分子克隆研究已确定了三种阿片受体类型：δ、κ 和 mu，它们可介导这些不同的作用(2,3)。人们对受体相互作用形成新功能结构的能力知之甚少，其中最简单的是二聚体，结构和生化研究表明其他 G 蛋白偶联受体 (GPCR) 相互作用形成同二聚体 (4,5)，此外，两个非功能性受体异二聚化形成功能性受体，表明二聚化对于受体功能至关重要 (6-11)。然而，两个全功能受体之间的异二聚化尚未被记录。在这里，我们提供了两种全功能阿片受体 kappa 和 delta 异二聚化的生化和药理学证据。这产生了一种新受体，其表现出与任一受体不同的配体结合和功能特性。此外，κ-δ异二聚体协同结合高选择性激动剂并增强信号转导。因此，这些 GPCR 的异二聚化代表了一种调节其功能的新机制。
The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function(1). Pharmacological and molecular cloning studies have identified three opioid-receptor types, delta, kappa and mu, that mediate these diverse effects(2,3). Little is known about the ability of the receptors to interact to form new functional structures, the simplest of which would be a dimer, Structural and biochemical studies show that other G-protein-coupled receptors (GPCRs) interact to form homodimers(4,5), Moreover, two nonfunctional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function(6-11). However, heterodimerization between two fully functional receptors has not been documented. Here we provide biochemical and pharmacological evidence for the heterodimerization of two fully functional opioid receptors, kappa and delta. This results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor. Furthermore, the kappa-delta heterodimer synergistically binds highly selective agonists and potentiates signal transduction. Thus, heterodimerization of these GPCRs represents a novel mechanism that modulates their function.