Brock Carsten, Oueslati Nadia, Soler Stéphan, Boudier Laure, Rondard Philippe, Pin Jean-Philippe
University of Montpellier 1 and 2, CNRS UMR 5203, Institute of Functional Genomics, 141 rue de la Cardonille, Montpellier, France.
J Biol Chem. 2007 Nov 9;282(45):33000-8. doi: 10.1074/jbc.M702542200. Epub 2007 Sep 13.
Although many G protein-coupled receptors (GPCRs) can form dimers, a possible role of this phenomenon in their activation remains elusive. A recent and exciting proposal is that a dynamic intersubunit interplay may contribute to GPCR activation. Here, we examined this possibility using dimeric metabotropic glutamate receptors (mGluRs). We first developed a system to perfectly control their subunit composition and show that mGluR dimers do not form larger oligomers. We then examined an mGluR dimer containing one subunit in which the extracellular agonist-binding domain was uncoupled from the G protein-activating transmembrane domain. Despite this uncoupling in one protomer, agonist stimulation resulted in symmetric activation of either transmembrane domain in the dimer with the same efficiency. This, plus other data, can only be explained by an intersubunit rearrangement as the activation mechanism. Although well established for other types of receptors such as tyrosine kinase and guanylate cyclase receptors, this is the first clear demonstration that such a mechanism may also apply to GPCRs.
尽管许多G蛋白偶联受体（GPCRs）能够形成二聚体，但这种现象在其激活过程中可能发挥的作用仍不清楚。最近有一个令人兴奋的观点认为，亚基间的动态相互作用可能有助于GPCR的激活。在此，我们利用二聚体代谢型谷氨酸受体（mGluRs）来研究这种可能性。我们首先开发了一个系统来完美控制其亚基组成，并证明mGluR二聚体不会形成更大的寡聚体。然后，我们研究了一种mGluR二聚体，其中一个亚基的细胞外激动剂结合结构域与G蛋白激活跨膜结构域解偶联。尽管在一个原体中存在这种解偶联，但激动剂刺激导致二聚体中任何一个跨膜结构域以相同效率对称激活。这一点以及其他数据只能通过亚基间重排作为激活机制来解释。尽管对于其他类型的受体，如酪氨酸激酶受体和鸟苷酸环化酶受体来说，这一机制已得到充分证实，但这是首次明确证明这种机制也可能适用于GPCRs。
