Elsevier

Neurobiology of Disease

Volume 159, November 2021, 105466
Neurobiology of Disease

Cytohesin-2 mediates group I metabotropic glutamate receptor-dependent mechanical allodynia through the activation of ADP ribosylation factor 6 in the spinal cord

https://doi.org/10.1016/j.nbd.2021.105466Get rights and content
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Highlights

  • Cytohesin-2 shows preferential perisynaptic localization in dorsal horn neurons.

  • Cytohesin-2 forms a complex with mGluR5 in dorsal horn.

  • Cytohesin-2 cKO mice exhibit reduced mechanical allodynia in CFA and CCI models.

  • Cytohesin inhibitor SecinH3 blocks allodynia and Arf6 activation in pain models.

  • Cytohesin-2 cKO mice exhibit reduced DHPG-induced allodynia and ERK1/2 activation.

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.

Keywords

Chronic pain
Dorsal horn
mGluR5
Arf6
Small GTPase
Membrane trafficking

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These authors contributed equally to this work.