title: The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling.
abstract: The MT2 receptor is a principal type of G protein-coupled receptor that mainly mediates the effects of melatonin. Deficits of melatonin/MT2 signaling have been found in many neurological disorders, including Alzheimer's disease, the most common cause of dementia in the elderly, suggesting that preservation of the MT2 receptor may be beneficial to these neurological disorders. However, direct evidence linking the MT2 receptor to cognition-related synaptic plasticity remains to be established. Here, we report that the MT2 receptor, but not the MT1 receptor, is essential for axonogenesis both in vitro and in vivo. We find that axon formation is retarded in MT2 receptor knockout mice, MT2-shRNA electroporated brain slices or primary neurons treated with an MT2 receptor selective antagonist. Activation of the MT2 receptor promotes axonogenesis that is associated with an enhancement in excitatory synaptic transmission in central neurons. The signaling components downstream of the MT2 receptor consist of the Akt/GSK-3β/CRMP-2 cascade. The MT2 receptor C-terminal motif binds to Akt directly. Either inhibition of the MT2 receptor or disruption of MT2 receptor-Akt binding reduces axonogenesis and synaptic transmission. Our data suggest that the MT2 receptor activates Akt/GSK-3β/CRMP-2 signaling and is necessary and sufficient to mediate functional axonogenesis and synaptic formation in central neurons.
authors.affiliation: 1] Department of Pathophyiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2] Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Key Laboratory of Neurological Diseases, Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [3] The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1] Department of Pathophyiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2] Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Key Laboratory of Neurological Diseases, Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [3] The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: N
authors.initials: N
authors.lastname: Wei
authors.affiliation: Department of Biology, Boston University, Boston, MA 02215, USA.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Man
authors.affiliation: 1] Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Key Laboratory of Neurological Diseases, Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2] The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 1] Department of Pathophyiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2] Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Key Laboratory of Neurological Diseases, Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [3] The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: L-Q
authors.initials: LQ
authors.lastname: Zhu
authors.affiliation: 1] Department of Pathophyiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2] Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Key Laboratory of Neurological Diseases, Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [3] The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: J-Z
authors.initials: JZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D036681:Fluorescence Recovery After Photobleaching; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: C114459:4-phenyl-2-propionamidotetraline; D034741:RNA, Small Interfering; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D013764:Tetrahydronaphthalenes; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D008550:Melatonin