Groeneweg Femke L, Trattnig Christa, Kuhse Jochen, Nawrotzki Ralph A, Kirsch Joachim
Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
Histochem Cell Biol. 2018 Nov;150(5):489-508. doi: 10.1007/s00418-018-1725-2. Epub 2018 Sep 27.
Scaffolding proteins underlying postsynaptic membrane specializations are important structural and functional components of both excitatory and inhibitory synapses. At inhibitory synapses, gephyrin was identified as anchoring protein. Gephyrin self-assembles into a complex flat submembranous lattice that slows the lateral mobility of glycine and GABA receptors, thus allowing for their clustering at postsynaptic sites. The structure and stability of the gephyrin lattice is dynamically regulated by posttranslational modifications and interactions with binding partners. As gephyrin is the core scaffolding protein for virtually all inhibitory synapses, any changes in the structure or stability of its lattice can profoundly change the packing density of inhibitory receptors and, therefore, alter inhibitory drive. Intriguingly, gephyrin plays a completely independent role in non-neuronal cells, where it facilitates two steps in the biosynthesis of the molybdenum cofactor. In this review, we provide an overview of the role of gephyrin at inhibitory synapses and beyond. We discuss its dynamic regulation, the nanoscale architecture of its synaptic lattice, and the implications of gephyrin dysfunction for neuropathologic conditions, such as Alzheimer's disease and epilepsy.
构成突触后膜特化结构的支架蛋白是兴奋性和抑制性突触重要的结构和功能组成部分。在抑制性突触中，桥连蛋白被确定为锚定蛋白。桥连蛋白自组装形成一个复杂的扁平膜下晶格，减缓甘氨酸和GABA受体的横向移动，从而使其在突触后位点聚集。桥连蛋白晶格的结构和稳定性受到翻译后修饰以及与结合伴侣相互作用的动态调控。由于桥连蛋白实际上是所有抑制性突触的核心支架蛋白，其晶格结构或稳定性的任何变化都可能深刻改变抑制性受体的堆积密度，进而改变抑制性驱动。有趣的是，桥连蛋白在非神经元细胞中发挥着完全独立的作用，它在钼辅因子的生物合成过程中促进两个步骤。在这篇综述中，我们概述了桥连蛋白在抑制性突触及其他方面的作用。我们讨论了其动态调控、突触晶格的纳米级结构，以及桥连蛋白功能障碍对神经病理状况（如阿尔茨海默病和癫痫）的影响。
