Heterodimerization of type A and B cholecystokinin receptors enhance signaling and promote cell growth
Heterodimerization of type A and B cholecystokinin receptors enhance signaling and promote cell growth
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DOI：
10.1074/jbc.m310090200
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发表时间：
2003-12-26
影响因子：
4.8
通讯作者：
Miller, LJ
中科院分区：
文献类型：
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作者：
Cheng, ZJ;Harikumar, KG;Miller, LJ
最近已经描述了几种G蛋白偶联受体的二聚化，但对其临床和功能相关性知之甚少。胆囊收缩素（CCK）和胃泌素是结构上相关的胃肠和神经肽，其功能由该超家族中的两种结构上相关的受体，A型和B型CCK受体介导。我们先前证明了A型CCK受体的自发同源二聚化和那些复合物通过激动剂占据的解离（Cheng，Z. J.，和米勒，L. J.（2001）J.Biol.Chem.276，48040-48047）。在这里，第一次，我们也证明自发同源二聚体的B型CCK受体，以及异源二聚体的受体与A型CCK受体。与A型CCK受体二聚体不同，B型CCK受体的同源二聚体不受配体占据的影响。然而，尽管A型和B型CCK受体的异二聚体正常结合天然激动剂，但它们表现出不寻常的功能和调节特性。此类复合物表现出增强的激动剂刺激的细胞信号传导和延迟的激动剂诱导的受体内化。作为一个可能的结果，激动剂刺激的细胞生长显着增强同时表达这两种受体的细胞。我们的研究结果首次证明了G蛋白偶联受体的异源二聚体可以形成一个更“强大”的信号单元，这在促进细胞生长方面具有潜在的临床意义。
Dimerization of several G protein-coupled receptors has recently been described, but little is known about its clinical and functional relevance. Cholecystokinin (CCK) and gastrin are structurally related gastrointestinal and neuronal peptides whose functions are mediated by two structurally related receptors in this superfamily, the type A and B CCK receptors. We previously demonstrated spontaneous homodimerization of type A CCK receptors and the dissociation of those complexes by agonist occupation (Cheng, Z. J., and Miller, L. J. (2001) J. Biol. Chem. 276, 48040-48047). Here, for the first time, we also demonstrate spontaneous homodimerization of type B CCK receptors, as well as heterodimerization of that receptor with the type A CCK receptor. Unlike type A CCK receptor dimers, the homodimerization of type B CCK receptors was not affected by ligand occupation. However, although heterodimers of type A and B CCK receptors bound natural agonists normally, they exhibited unusual functional and regulatory characteristics. Such complexes demonstrated enhanced agonist-stimulated cellular signaling and delayed agonist-induced receptor internalization. As a likely consequence, agonist-stimulated cell growth was markedly enhanced in cells simultaneously expressing both of these receptors. Our results provide the first evidence that heterodimerization of G protein-coupled receptors can form a more "powerful" signaling unit, which has potential clinical significance in promoting cell growth.