Activation of CaMKII and GluR1 by the PSD-95-GluN2B Coupling-Dependent Phosphorylation of GluN2B in the Spinal Cord in a Rat Model of Type-2 Diabetic Neuropathic Pain

Zhu, Yabing; Jia, Gai Li; Wang, Jun Wu; Ye, Xiu Ying; Jia, Lan; Chen, Jia Li; Zhang, Mao Biao; Xie, Ci Shan; Shen, Yu; Tao, Yuan Xiang; Li, Jun; Cao, Hong

doi:10.1093/jnen/nlaa035

Cited by 17 publications

(16 citation statements)

References 36 publications

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“… 42 GluR1 is mainly expressed in superficial layer of spinal dorsal horn and funtion as an initial part of the signal related to the transmission and regulation of pain. 43 In this study, our result showed that the phosphorylated form of both Rac1 (p‐Rac1) and GluR1 (p-GluR1) was significantly increased in the BCP group than in the sham group. Treatment with shP-Rex2 significantly inhibited the upregulation of p‐Rac1 and pGluR1 in the BCP group.…”

Section: Discussionmentioning

confidence: 50%

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain

Huang²,

Li³

et al. 2022

Mol Pain

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Bone cancer pain (BCP) seriously affects the quality of life, however, due to its complex mechanism the clinical treatment was unsatisfactory. Recent studies have showed several Rac-specific guanine nucleotide exchange factor (GEF) that affect development and structure of neuronal processes play a vital role in the regulation of chronic pain. P-Rex2 is one of GEFs that regulate spine density, and the present study was performed to examine the effect of P-Rex2 on the development of BCP. Tumor cells implantation induced the mechanical hyperalgesia, which was accompanied by an increase in spinal protein P-Rex2, phosphorylated Rac1 (p-Rac1) and phosphorylated GluR1 (p-GluR1), and number of spines. Intrathecal injection a P-Rex2-targeting RNAi lentivirus relieved BCP and reduced the expression of P-Rex2, p-Rac1, p-GluR1and number of spines in the BCP mice. Meanwhile, P-Rex2 knockdown reversed BCP-enhanced AMPA receptor (AMPAR)-induced current in dorsal horn neurons. In summary, this study suggested that P-Rex2 regulated GluR1-containing AMPAR trafficking and spine morphology via Rac1/pGluR1 pathway is a fundamental pathogenesis of BCP. Our findings provide a better understanding of the function of P-Rex2 as a possible therapeutic target for relieving BCP.

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Section: Discussionmentioning

confidence: 50%

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain

Huang²,

Li³

et al. 2022

Mol Pain

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“…In HFD/STZ models, insulin was reported to be decreased [ 40 ], increased [ 41 ], and unchanged [ 42 , 43 ] at 16 weeks with no clear relationship to DPN phenotype ( Table 2 ). In HFHS/STZ models, four studies [ 44 - 47 ] demonstrated an increase in insulin that corresponded with mechanical or thermal hyperalgesia. However, all these studies were of short duration (<5 weeks) where hyperalgesia is common ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions

et al. 2022

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Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the ‘Neurodiab’ criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.

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“…Both AMPAR levels at synapses and AMPAR-dependent synaptic transmission are reduced in hippocampal slices of newborn NL1 knockout mice (Zhu et al, 2020). A unique intracellular tyrosine in NL1 regulates AMPAR recruitment during synapse differentiation and potentiation (Letellier et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Neuroligin1 Contributes to Neuropathic Pain by Promoting Phosphorylation of Cofilin in Excitatory Neurons

Ouyang

Chen

et al. 2021

Front. Mol. Neurosci.

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Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4–L6 spinal dorsal horn in Vglut2-cre+/– mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre+/– mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.

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Activation of CaMKII and GluR1 by the PSD-95-GluN2B Coupling-Dependent Phosphorylation of GluN2B in the Spinal Cord in a Rat Model of Type-2 Diabetic Neuropathic Pain

Cited by 17 publications

References 36 publications

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain

Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions

Neuroligin1 Contributes to Neuropathic Pain by Promoting Phosphorylation of Cofilin in Excitatory Neurons

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