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Gephyrin: a key regulatory protein of inhibitory synapses and beyond

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Abstract

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 GABAA 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.

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  1. Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany

    Femke L. Groeneweg, Christa Trattnig, Jochen Kuhse, Ralph A. Nawrotzki & Joachim Kirsch

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Groeneweg, F.L., Trattnig, C., Kuhse, J. et al. Gephyrin: a key regulatory protein of inhibitory synapses and beyond. Histochem Cell Biol 150, 489–508 (2018). https://doi.org/10.1007/s00418-018-1725-2

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