1. Cytohesin-2 mediates group I metabotropic glutamate receptor-dependent mechanical allodynia through the activation of ADP ribosylation factor 6 in the spinal cord.
- Author
-
Ito A, Fukaya M, Sugawara T, Hara Y, Okamoto H, Yamauchi J, and Sakagami H
- Subjects
- ADP-Ribosylation Factor 1 drug effects, ADP-Ribosylation Factor 1 metabolism, ADP-Ribosylation Factor 6 drug effects, Animals, GTPase-Activating Proteins antagonists & inhibitors, GTPase-Activating Proteins metabolism, Hyperalgesia metabolism, Inflammation genetics, Inflammation metabolism, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System genetics, Methoxyhydroxyphenylglycol analogs & derivatives, Methoxyhydroxyphenylglycol pharmacology, Mice, Mice, Knockout, Neuralgia metabolism, Post-Synaptic Density metabolism, Posterior Horn Cells drug effects, Receptor, Metabotropic Glutamate 5 agonists, Receptors, Metabotropic Glutamate agonists, Spinal Cord drug effects, Spinal Cord Dorsal Horn, Triazoles pharmacology, ADP-Ribosylation Factor 6 metabolism, GTPase-Activating Proteins genetics, Hyperalgesia genetics, Neuralgia genetics, Posterior Horn Cells metabolism, Receptor, Metabotropic Glutamate 5 metabolism, Spinal Cord metabolism
- Abstract
Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, in the spinal cord are implicated in nociceptive transmission and plasticity through G protein-mediated second messenger cascades leading to the activation of various protein kinases such as extracellular signal-regulated kinase (ERK). In this study, we demonstrated that cytohesin-2, a guanine nucleotide exchange factor for ADP ribosylation factors (Arfs), is abundantly expressed in subsets of excitatory interneurons and projection neurons in the superficial dorsal horn. Cytohesin-2 is enriched in the perisynapse on the postsynaptic membrane of dorsal horn neurons and forms a protein complex with mGluR5 in the spinal cord. Central nervous system-specific cytohesin-2 conditional knockout mice exhibited reduced mechanical allodynia in inflammatory and neuropathic pain models. Pharmacological blockade of cytohesin catalytic activity with SecinH3 similarly reduced mechanical allodynia and inhibited the spinal activation of Arf6, but not Arf1, in both pain models. Furthermore, cytohesin-2 conditional knockout mice exhibited reduced mechanical allodynia and ERK1/2 activation following the pharmacological activation of spinal mGluR1/5 with 3,5-dihydroxylphenylglycine (DHPG). The present study suggests that cytothesin-2 is functionally associated with mGluR5 during the development of mechanical allodynia through the activation of Arf6 in spinal dorsal horn neurons., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF