Signal flow in the NMDA receptor-dependent phosphoproteome regulates postsynaptic plasticity for aversive learning.

Autor: Funahashi Y; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Ahammad RU; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Alzheimer's Therapeutic Research Institute, Keck School of Medicine of the University of Southern California, San Diego, CA 92121, USA., Zhang X; Division of Behavioral Neuropharmacology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Hossen E; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Kawatani M; Department of Physiology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan., Nakamuta S; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Yoshimi A; Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.; Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, Nagoya, Aichi 468-8503, Japan., Wu M; Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Wang H; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Wu M; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Li X; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Faruk MO; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Shohag MH; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Lin YH; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Tsuboi D; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Nishioka T; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Kuroda K; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Amano M; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Noda Y; Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.; Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, Nagoya, Aichi 468-8503, Japan., Yamada K; Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Sakimura K; Brain Research Institute, Niigata University, Niigata 951-8585, Japan., Nagai T; Division of Behavioral Neuropharmacology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Yamashita T; Department of Physiology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.; Division of Neurophysiology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan., Uchino S; Department of Biosciences, School of Science and Engineering, Teikyo University, Utsunomiya, Tochigi 320-8551, Japan., Kaibuchi K; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.; Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2024 Sep 10; Vol. 17 (853), pp. eado9852. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1126/scisignal.ado9852
Abstrakt: Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca 2+ -dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca 2+ -dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.
Databáze: MEDLINE
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