Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York.
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York
Mol Pharmacol. 2024 Jan 10;105(2):104-115. doi: 10.1124/molpharm.123.000795.
Metabotropic glutamate receptors (mGluRs) are obligate dimer G protein coupled receptors that can all function as homodimers. Here, each mGluR homodimer was examined for its G protein coupling profile using a bioluminescence resonance energy transfer-based assay that detects the interaction between a split YFP-tagged G γ and a Nanoluciferase tagged free Gγ sensor, MAS-GRK3-ct- nanoluciferase with 14 specific Gα proteins heterologously expressed, representing each family. Canonically, the group II and III mGluRs (2 and 3 and 4, 6, 7, and 8, respectively) are thought to couple to G exclusively. In addition, the group I mGluRs (1 and 5) are known to couple to the G family and generally thought to also couple to the pertussis toxin-sensitive G family some reports have suggested G coupling is possible as cAMP elevations have been noted. In this study, coupling was observed with all eight mGluRs through the G proteins and only mGluR1 and mGluR5 through G, and, perhaps surprisingly, not G None activated any G protein. Interestingly, coupling was seen with the group I and II but not the group III mGluRs to G Slow but significant coupling to G was also seen with the group II receptors. SIGNIFICANCE STATEMENT: Metabotropic glutamate receptor (mGluR)-G protein coupling has not been thoroughly examined, and some controversy remains about whether some mGluRs can activate G family members. Here we examine the ability of each mGluR to activate representative members of every G protein family. While all mGluRs can activate G proteins, only the group I mGluRs couple to G, and no members of the family can activate G family members, including the group I receptors alone or with positive allosteric modulators.
代谢型谷氨酸受体（mGluRs）是必需的二聚体 G 蛋白偶联受体，它们都可以作为同源二聚体发挥作用。在这里，使用基于生物发光共振能量转移的测定法检查每个 mGluR 同源二聚体的 G 蛋白偶联谱，该测定法检测分裂的 YFP 标记的 Gγ 和 Nanoluciferase 标记的游离 Gγ 传感器之间的相互作用，MAS-GRK3-ct-nanoluciferase 与 14 种异源表达的特定 Gα 蛋白一起使用，代表每个家族。通常认为，第二组和第三组 mGluRs（2、3 和 4、6、7 和 8 分别）仅与 G 偶联。此外，已知第一组 mGluRs（1 和 5）与 G 家族偶联，并且通常认为也与百日咳毒素敏感的 G 家族偶联，一些报告表明 G 偶联是可能的，因为已经注意到 cAMP 升高。在这项研究中，通过 G 蛋白观察到所有 8 种 mGluRs 的偶联，并且仅通过 G 蛋白观察到 mGluR1 和 mGluR5 的偶联，并且也许令人惊讶的是，没有 G 蛋白激活任何 G 蛋白。有趣的是，在第一组和第二组中观察到偶联，但在第三组 mGluRs 中未观察到偶联到 G 蛋白。对 G 蛋白的偶联也观察到了缓慢但显著的作用，并且在第二组受体中也观察到了对 G 蛋白的偶联。意义陈述：代谢型谷氨酸受体（mGluR）-G 蛋白偶联尚未得到彻底研究，关于某些 mGluR 是否可以激活 G 家族成员仍存在一些争议。在这里，我们检查每个 mGluR 激活每种 G 蛋白家族代表成员的能力。虽然所有 mGluRs 都可以激活 G 蛋白，但只有第一组 mGluRs 与 G 偶联，并且家族的任何成员都不能激活 G 家族成员，包括第一组受体本身或与正变构调节剂一起使用。
