Novel contribution of cell surface and intracellular M1‐muscarinic acetylcholine receptors to synaptic plasticity in hippocampus |
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Authors: | Hatsumi Yoshiki Matomo Nishio Yuji Ikegaya Naoya Takahashi Norio Matsuki Yasuhisa Fujibayashi Yoshiharu Yonekura Toshihiko Momiyama Ikunobu Muramatsu |
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Affiliation: | 1. Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, , Eiheiji, Japan;2. Department of Pharmacology, School of Medicine, Kanazawa Medical University, , Uchinada, Japan;3. Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, , Hongo Bunkyo‐ku, Japan;4. Biomedical Imaging Research Center, University of Fukui, , Eiheiji, Japan;5. Department of Pharmacology, Jikei University School of Medicine, , Minato‐ku, Japan;6. Organization for Life Science Advancement Programs, University of Fukui, , Eiheiji, Japan;7. Child Development Research Center, Graduate School of Medicine, University of Fukui, , Eiheiji, Japan |
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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. |
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Keywords: | cell surface and intracellular GPCR ERK1/2
LTP
M1‐muscarinic receptor synaptic plasticity |
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