Department of Biochemistry and Physiology of the Faculty of Pharmacy of the University of Barcelona, 08028, Barcelona, Spain.
Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network, 08028, Barcelona, Spain.
Nat Commun. 2018 Mar 28;9(1):1242. doi: 10.1038/s41467-018-03522-3.
G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of heteromers of adenosine A receptor and dopamine D receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR.
G 蛋白偶联受体（GPCRs）、G 蛋白和腺苷酸环化酶（AC）构成了研究最广泛的跨膜细胞信号转导途径之一。然而，这些信号分子之间的配体依赖性相互作用是基于随机碰撞还是大分子复合物中预先偶联元件的重排尚不清楚。此外，一个 GPCR 同源二聚体与单个异三聚体 G 蛋白偶联是否构成一个常见的功能单元仍存在争议。本研究采用基于肽的方法，报告了腺苷 A 受体和多巴胺 D 受体同源二聚体与各自的 Gs 和 Gi 蛋白以及亚型 5 AC 异源三聚体的功能预偶联复合物存在的证据。我们还证明，这个大分子复合物为 AC 水平上的经典 Gs-Gi 相互作用提供了必要的框架，维持了 Gi 偶联 GPCR 对抗由 Gs 偶联 GPCR 介导的 AC 激活的能力。
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