Membrane trafficking processes regulate G protein–coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT_2A receptors (5-HT_2ARs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through a mechanism that required their assembly as heteromers in mammalian cells. In the absence of agonists, 5-HT_2AR was primarily localized within intracellular compartments, and coexpression of 5-HT_2AR with mGluR2 increased the intracellular distribution of the otherwise plasma membrane–localized mGluR2. Agonists for either 5-HT_2AR or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT_2AR–mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT_2AR blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT_2AR and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT_2AR–mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT_2AR–dependent effects on mGluR2 subcellular distribution. The expression of 5-HT_2AR also augmented intracellular localization of mGluR2 in mouse frontal cortex pyramidal neurons. Together, our data suggest that GPCR heteromerization may itself represent a mechanism of receptor trafficking and sorting.

膜运输过程调节 G 蛋白偶联受体 (GPCR) 活性。尽管 A 类 GPCR 能够以单体形式激活 G 蛋白，但它们也可能组装成功能性 GPCR 异聚体。在这里，我们展示了 A 类血清素 5-HT _2A受体 (5-HT _2A Rs) 通过需要它们作为异聚体在哺乳动物细胞中组装的机制影响 C 类代谢型谷氨酸受体 2 (mGluR2) 的定位和运输。在没有激动剂的情况下，5-HT _2A R 主要定位在细胞内隔室中，5-HT _2A R 与 mGluR2 的共表达增加了其他质膜定位的 mGluR2 的细胞内分布。5-HT 的激动剂_2A R 或 mGluR2 不同地影响通过 Rab5 阳性内体在单独或一起表达 5-HT _2A R–mGluR2异源复合物的每个组分的细胞中的运输。此外，使用氯氮平（而不是 M100907）隔夜药理学 5-HT _2A R 阻断，通过涉及 5-HT _2A R 和 mGluR2之间的异聚化的机制降低了 mGluR2 密度。使用无法形成类间 5-HT _2A R-mGluR2 复合物的TAT 标记肽和嵌合构建体，我们证明了异聚化对于 5-HT _2A R 依赖性对 mGluR2 亚细胞分布的影响是必要的。5-HT _2A的表达R 还增强了小鼠额叶皮层锥体神经元中 mGluR2 的细胞内定位。总之，我们的数据表明 GPCR 异聚化本身可能代表了受体运输和分类的机制。