Integrative Neurobiology Section, USA.
Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain.
Pharmacol Res. 2022 Aug;182:106322. doi: 10.1016/j.phrs.2022.106322. Epub 2022 Jun 22.
Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal receptors (GalRs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and GalR when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the GalR homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-GalR heterotetramer, which is thus bound to Gs via the GalR homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.
最近的研究提出，位于中脑的μ-阿片受体（MOR）和甘丙肽 Gal 受体（GalR）异源二聚体介导阿片类药物的多巴胺能效应。本研究使用肽干扰方法结合生物物理和生化技术，包括全内反射荧光显微镜，报告了趋同的证据，证明当单独表达时，MOR 和 GalR 具有主要的同源二聚体结构，并且当共表达时，它们优先形成功能性异四聚体。结果表明，GalR 同源二聚体界面的异源二聚化依赖性变化导致 G 蛋白偶联从抑制性 Gi 向刺激性 Gs 蛋白的转变。因此，通过 GalR 同源二聚体结合 Gs 并通过 MOR 同源二聚体结合 Gi 的 MOR-GalR 异四聚体为腺苷酸环化酶水平的经典 Gs-Gi 拮抗剂相互作用提供了框架。这些新的结果阐明了关于 G 蛋白偶联受体的寡聚四级结构、它们对异源二聚体形成的偏好以及由此产生的功能意义的激烈争论。
