Rho-Kinase/ROCK Phosphorylates PSD-93 Downstream of NMDARs to Orchestrate Synaptic Plasticity

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  • Emran Hossen
    Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
  • Yasuhiro Funahashi
    Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake 470-1192, Japan
  • Md. Omar Faruk
    Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
  • Rijwan Uddin Ahammad
    Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
  • Mutsuki Amano
    Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
  • Kiyofumi Yamada
    Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
  • Kozo Kaibuchi
    Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan

Description

<jats:p>The N-methyl-D-aspartate receptor (NMDAR)-mediated structural plasticity of dendritic spines plays an important role in synaptic transmission in the brain during learning and memory formation. The Rho family of small GTPase RhoA and its downstream effector Rho-kinase/ROCK are considered as one of the major regulators of synaptic plasticity and dendritic spine formation, including long-term potentiation (LTP). However, the mechanism by which Rho-kinase regulates synaptic plasticity is not yet fully understood. Here, we found that Rho-kinase directly phosphorylated discs large MAGUK scaffold protein 2 (DLG2/PSD-93), a major postsynaptic scaffold protein that connects postsynaptic proteins with NMDARs; an ionotropic glutamate receptor, which plays a critical role in synaptic plasticity. Stimulation of striatal slices with an NMDAR agonist induced Rho-kinase-mediated phosphorylation of PSD-93 at Thr612. We also identified PSD-93-interacting proteins, including DLG4 (PSD-95), NMDARs, synaptic Ras GTPase-activating protein 1 (SynGAP1), ADAM metallopeptidase domain 22 (ADAM22), and leucine-rich glioma-inactivated 1 (LGI1), by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among them, Rho-kinase increased the binding of PSD-93 to PSD-95 and NMDARs. Furthermore, we found that chemical-LTP induced by glycine, which activates NMDARs, increased PSD-93 phosphorylation at Thr612, spine size, and PSD-93 colocalization with PSD-95, while these events were blocked by pretreatment with a Rho-kinase inhibitor. These results indicate that Rho-kinase phosphorylates PSD-93 downstream of NMDARs, and suggest that Rho-kinase mediated phosphorylation of PSD-93 increases the association with PSD-95 and NMDARs to regulate structural synaptic plasticity.</jats:p>

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