Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation

Yuko Fukata; Yoko Hirano; Yuri Miyazaki; Norihiko Yokoi; Masaki Fukata

doi:10.1016/j.neuropharm.2021.108628

Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation

Neuropharmacology. 2021 Aug 15:194:108628. doi: 10.1016/j.neuropharm.2021.108628. Epub 2021 Jun 3.

Authors

Yuko Fukata¹, Yoko Hirano², Yuri Miyazaki¹, Norihiko Yokoi¹, Masaki Fukata³

Affiliations

¹ 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.
² 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.
³ 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. Electronic address: mfukata@nips.ac.jp.

PMID: 34089731
DOI: 10.1016/j.neuropharm.2021.108628

Abstract

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.

Keywords: ADAM22; AMPA receptor; Epilepsy; LGI1; Limbic encephalitis; MAGUK; NMDA receptor; Synapse; Trans-synaptic nanocolumn.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

ADAM Proteins / metabolism*
Animals
Brain / metabolism
Epilepsy / metabolism
Guanylate Kinases / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Nerve Tissue Proteins / metabolism*
Receptors, AMPA / metabolism*
Receptors, N-Methyl-D-Aspartate / metabolism*
Synapses / metabolism*
Synaptic Transmission

Substances

Intracellular Signaling Peptides and Proteins
LGI1 protein, human
Nerve Tissue Proteins
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
Guanylate Kinases
ADAM Proteins
ADAM22 protein, human