Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer
Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer
复制标题
DOI：
10.1038/35082096
复制
发表时间：
2001-06-21
期刊：
影响因子：
64.8
通讯作者：
Fagni, L
中科院分区：
文献类型：
--
作者：
Ango, F;Prézeau, L;Fagni, L
G蛋白偶联受体（GPCRs）通过激活G蛋白将细胞外递质的信号转导至细胞内部。这些受体的突变和过表达表明，由于其非活性构象和活性构象之间的平衡发生自然偏移，即使在没有激动剂的情况下它们也能达到活性状态（1）。当谷氨酸GPCRs（代谢型谷氨酸受体mGluR1a和mGluR5）在异源细胞中过表达时，已经观察到这种不依赖激动剂的（组成型）活性（2）。在此我们表明，在神经元中，这些受体的组成型活性受Homer蛋白控制，Homer蛋白直接与受体的羧基末端胞内结构域结合（3,4）。通过诱变或反义策略破坏这种相互作用，或者内源性Homer1a（H1a）的表达，会诱导mGluR1a或mGluR5的组成型活性。我们的结果表明，这些谷氨酸GPCRs既能被细胞内蛋白也能被激动剂直接激活。
G-protein-coupled receptors (GPCRs) transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations(1). Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells(2). Here we show that in neurons, the constitutive activity of these receptors is controlled by Homer proteins, which bind directly to the receptors' carboxy-terminal intracellular domains(3,4). Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5. Our results show that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.