Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, Würzburg, Germany.
Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan.
Sci Adv. 2020 Apr 15;6(16):eaay7193. doi: 10.1126/sciadv.aay7193. eCollection 2020 Apr.
G protein-coupled receptors (GPCRs) play a fundamental role in the modulation of synaptic transmission. A pivotal example is provided by the metabotropic glutamate receptor type 4 (mGluR4), which inhibits glutamate release at presynaptic active zones (AZs). However, how GPCRs are organized within AZs to regulate neurotransmission remains largely unknown. Here, we applied two-color super-resolution imaging by stochastic optical reconstruction microscopy (STORM) to investigate the nanoscale organization of mGluR4 at parallel fiber AZs in the mouse cerebellum. We find an inhomogeneous distribution, with multiple nanodomains inside AZs, each containing, on average, one to two mGluR4 subunits. Within these nanodomains, mGluR4s are often localized in close proximity to voltage-dependent Ca2.1 channels and Munc-18-1, which are both essential for neurotransmitter release. These findings provide previously unknown insights into the molecular organization of GPCRs at AZs, suggesting a likely implication of a close association between mGluR4 and the secretory machinery in modulating synaptic transmission.
G 蛋白偶联受体 (GPCRs) 在调节突触传递中发挥着基本作用。代谢型谷氨酸受体 4 (mGluR4) 就是一个重要的例子，它在突触前活性区 (AZ) 抑制谷氨酸释放。然而，GPCRs 如何在 AZ 内组织以调节神经递质传递在很大程度上仍然未知。在这里，我们应用双色超分辨率成像技术通过随机光学重建显微镜 (STORM) 来研究小鼠小脑颗粒细胞平行纤维 AZ 上 mGluR4 的纳米级组织。我们发现存在不均匀的分布，在 AZ 内有多个纳米域，每个纳米域平均包含一到两个 mGluR4 亚基。在这些纳米域内，mGluR4 通常与电压依赖性 Ca2.1 通道和 Munc-18-1 紧密接近定位，这两者对于神经递质释放都是必不可少的。这些发现为 AZ 上 GPCRs 的分子组织提供了前所未知的见解，表明 mGluR4 与分泌机制之间的密切关联可能在调节突触传递中起重要作用。
