Trans-synaptic LGI1–ADAM22–MAGUK in AMPA and NMDA receptor regulation. (15th August 2021)

• Record Type: Journal Article
• Authors: Fukata, Yuko; Hirano, Yoko; Miyazaki, Yuri; Yokoi, Norihiko; Fukata, Masaki
• Is Part Of: Neuropharmacology. Volume 194(2021)
• Publication Date: 2021-08-15
• Subjects: LGI1 -- ADAM22 -- MAGUK -- AMPA receptor -- NMDA receptor -- Synapse -- Epilepsy -- Limbic encephalitis -- Trans-synaptic nanocolumn; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2021.108628
• Languages: English
• ISSNs: 0028-3908

Abstract

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. This article is part of the Neuropharmacology Special Issue on 'Glutamate Receptors – AMPA receptors'. Highlights: LGI1–ADAM22–MAGUK organizes supercomplexes containing pre- and postsynaptic proteins LGI1–ADAM22–MAGUK is an essential component of trans -synaptic nanocolumns LGI1–ADAM22 controls PSD-95 MAGUK functions for glutamate receptors and Kv1 channels Disruption of LGI1–ADAM22–MAGUK linkage causes epilepsy