Fukata Yuko, Hirano Yoko, Miyazaki Yuri, Yokoi Norihiko, Fukata Masaki
Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, 444-8585, Japan.
Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.
Neuropharmacology. 2021 Aug 15;194:108628. doi: 10.1016/j.neuropharm.2021.108628. Epub 2021 Jun 3.
Exquisitely-regulated synaptic transmission and plasticity underlie higher brain functions such as learning and memory. PSD-95, a member of the MAGUK family, scaffolds an array of postsynaptic proteins including AMPA and NMDA receptors, and plays essential roles in excitatory synaptic transmission and postsynaptic organization. Epilepsy-related secreted protein LGI1 and its receptor ADAM22 represent major constituent elements of the PSD-95-containing synaptic protein complex in the brain. Recent studies begin to reveal a trans-synaptic configuration of the LGI1-ADAM22 complex and its pivotal role in AMPA and NMDA receptor-mediated synaptic transmission through regulating MAGUKs. Especially interesting is that without the association with LGI1-ADAM22, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Here, we review roles of LGI1-ADAM22 in synaptic function, and discuss its modes of action on the MAGUK regulation: as (i) a trans-synaptic hub, (ii) an extracellular scaffold, and (iii) an allosteric activator. We also highlight patho-physiological roles of the LGI1-ADAM22-MAGUK linkage in synaptic disorders such as epilepsy and autoimmune limbic encephalitis.
精确调控的突触传递和可塑性是学习和记忆等高级脑功能的基础。PSD-95是MAGUK家族的成员，它搭建了包括AMPA和NMDA受体在内的一系列突触后蛋白的支架，并在兴奋性突触传递和突触后组织中发挥重要作用。癫痫相关分泌蛋白LGI1及其受体ADAM22是大脑中含PSD-95的突触蛋白复合物的主要组成成分。最近的研究开始揭示LGI1-ADAM22复合物的跨突触结构及其通过调节MAGUKs在AMPA和NMDA受体介导的突触传递中的关键作用。特别有趣的是，没有与LGI1-ADAM22结合，PSD-95就不能增强AMPA受体介导的突触传递。在这里，我们综述了LGI1-ADAM22在突触功能中的作用，并讨论了其对MAGUK调节的作用方式：（i）作为跨突触枢纽，（ii）作为细胞外支架，以及（iii）作为变构激活剂。我们还强调了LGI1-ADAM22-MAGUK联系在癫痫和自身免疫性边缘性脑炎等突触疾病中的病理生理作用。
