title: Novel contribution of cell surface and intracellular M1-muscarinic acetylcholine receptors to synaptic plasticity in hippocampus.
abstract: Muscarinic acetylcholine receptors (mAChRs) are well known to transmit extracellular cholinergic signals into the cytoplasm from their position on the cell surface. However, we show here that M1-mAChRs are also highly expressed on intracellular membranes in neurons of the telencephalon and activate signaling cascades distinct from those of cell surface receptors, contributing uniquely to synaptic plasticity. Radioligand-binding experiments with cell-permeable and -impermeable ligands and immunohistochemical observations revealed intracellular and surface distributions of M1-mAChRs in the hippocampus and cortex of rats, mice, and humans, in contrast to the selective occurrence on the cell surface in other tissues. All intracellular muscarinic-binding sites were abolished in M1-mAChR-gene-knockout mice. Activation of cell surface M1-mAChRs in rat hippocampal neurons evoked phosphatidylinositol hydrolysis and network oscillations at theta rhythm, and transiently enhanced long-term potentiation. On the other hand, activation of intracellular M1-mAChRs phosphorylated extracellular-regulated kinase 1/2 and gradually enhanced long-term potentiation. Our data thus demonstrate that M1-mAChRs function at both surface and intracellular sites in telencephalon neurons including the hippocampus, suggesting a new mode of cholinergic transmission in the central nervous system.
authors.affiliation: Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Japan.
authors.forename: Abu Syed Md
authors.initials: AS
authors.lastname: Anisuzzaman
authors.forename: Junsuke
authors.initials: J
authors.lastname: Uwada
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Masuoka
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Yoshiki
authors.forename: Matomo
authors.initials: M
authors.lastname: Nishio
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.forename: Naoya
authors.initials: N
authors.lastname: Takahashi
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuki
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Yonekura
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Momiyama
authors.forename: Ikunobu
authors.initials: I
authors.lastname: Muramatsu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D043643:Receptor, Muscarinic M1
keywords: ERK1/2; LTP; M1-muscarinic receptor; cell surface and intracellular GPCR; synaptic plasticity