title: Neuromodulatory effect of Gαs- or Gαq-coupled G-protein-coupled receptor on NMDA receptor selectively activates the NMDA receptor/Ca2+/calcineurin/cAMP response element-binding protein-regulated transcriptional coactivator 1 pathway to effectively induce brain-derived neurotrophic factor expression in neurons.
abstract: Although coordinated molecular signaling through excitatory and modulatory neurotransmissions is critical for the induction of immediate early genes (IEGs), which lead to effective changes in synaptic plasticity, the intracellular mechanisms responsible remain obscure. Here we measured the expression of IEGs and used bioluminescence imaging to visualize the expression of Bdnf when GPCRs, major neuromodulator receptors, were stimulated. Stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor (PAC1), a Gαs/q-protein-coupled GPCR, with PACAP selectively activated the calcineurin (CN) pathway that is controlled by calcium signals evoked via NMDAR. This signaling pathway then induced the expression of Bdnf and CN-dependent IEGs through the nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1). Intracerebroventricular injection of PACAP and intraperitoneal administration of MK801 in mice demonstrated that functional interactions between PAC1 and NMDAR induced the expression of Bdnf in the brain. Coactivation of NMDAR and PAC1 synergistically induced the expression of Bdnf attributable to selective activation of the CN pathway. This CN pathway-controlled expression of Bdnf was also induced by stimulating other Gαs- or Gαq-coupled GPCRs, such as dopamine D1, adrenaline β, CRF, and neurotensin receptors, either with their cognate agonists or by direct stimulation of the protein kinase A (PKA)/PKC pathway with chemical activators. Thus, the GPCR-induced expression of IEGs in coordination with NMDAR might occur via the selective activation of the CN/CRTC1/CREB pathway under simultaneous excitatory and modulatory synaptic transmissions in neurons if either the Gαs/adenylate cyclase/PKA or Gαq/PLC/PKC-mediated pathway is activated.
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences.
authors: Mamoru
authors: M
authors: Fukuchi
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences.
authors: Akiko
authors: A
authors: Tabuchi
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences.
authors: Yuki
authors: Y
authors: Kuwana
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences.
authors: Shinjiro
authors: S
authors: Watanabe
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences.
authors: Minami
authors: M
authors: Inoue
authors: Division of Molecular Genetics Research, Life Science Research Center, and.
authors: Ichiro
authors: I
authors: Takasaki
authors: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Hironori
authors: H
authors: Izumi
authors: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Ayumi
authors: A
authors: Tanaka
authors: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Ran
authors: R
authors: Inoue
authors: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Hisashi
authors: H
authors: Mori
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical, Fujisawa, Kanagawa 251-8555, Japan.
authors: Hidetoshi
authors: H
authors: Komatsu
authors: Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Saito, Ibaraki, Osaka 567-0085, Japan, and.
authors: Hiroshi
authors: H
authors: Takemori
authors: Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Hiroyuki
authors: H
authors: Okuno
authors: Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Haruhiko
authors: H
authors: Bito
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, tsuda@pha.u-toyama.ac.jp.
authors: Masaaki
authors: M
authors: Tsuda
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018691:Excitatory Amino Acid Antagonists; D017874:Immediate-Early Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016194:Receptors, N-Methyl-D-Aspartate; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D014157:Transcription Factors; D019703:Calcineurin; D002118:Calcium
keywords: BDNF; CRTC1; GPCR; NMDAR; PACAP; calcineurin