The emerging role of kainate receptor functional dysregulation in pain

Li, Huili; Li, Junfa; Guan, Yun; Wang, Yun

doi:10.1177/1744806921990944

Cited by 3 publications

(4 citation statements)

References 115 publications

(149 reference statements)

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“…43 Moreover, KA-R regulates synaptic transmission at both excitatory and inhibitory synapses in the spinal cord dorsal horn. [44][45][46] Here we confirmed that both the amplitude and frequency of KA-R-mediated mEPSCs were increased in remifentanil group, miR-134-3p could partly reverse remifentanil induced mEPSCs amplification. Intrathecal injection of ACET, a potent and selective KA-R antagonist, was able to reverse the GRIK3 membrane trafficking and relieved RIH.…”

Section: Discussionsupporting

confidence: 74%

Spinal microRNA-134-5p targets glutamate receptor ionotropic kainate 3 to modulate opioid induced hyperalgesia in mice

et al. 2023

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Background: Fentanyl and its analogs are extensively used for pain relief. However, their paradoxically pronociceptive effects often lead to increased opioids consumption and risk of chronic pain. Compared to other synthetic opioids, remifentanil has been strongly linked to acute opioid hyperalgesia after exposure [remifentanil-induced hyperalgesia (RIH)]. The epigenetic regulation of microRNAs (miRNAs) on targeted mRNAs has emerged as an important pathogenesis in pain. The current research aimed at exploring the significance and contributions of miR-134-5p to the development of RIH. Methods: Both the antinociceptive and pronociceptive effects of two commonly used opioids were assessed, and miRNA expression profiles in the spinal dorsal horn (SDH) of mice acutely exposed to remifentanil and remifentanil equianalgesic dose (RED) sufentanil were screened. Next, the candidate miRNA level, cellular distribution, and function were examined by qPCR, fluorescent in situ hybridization (FISH) and Argonaute-2 immunoprecipitation. Furthermore, bioinformatics analysis, luciferase assays, miRNA overexpression, behavioral tests, golgi staining, electron microscopy, whole-cell patch-clamp recording, and immunoblotting were employed to investigate the potential targets and mechanisms underlying RIH. Results: Remifentanil induced significant pronociceptive effects and a distinct miRNA-profile from sufentanil when compared to saline controls. Among top 30 differentially expressed miRNAs spectrum, spinal miR-134-5p was dramatically downregulated in RIH mice but remained comparative in mice subjected to sufentanil. Moreover, Glutamate Receptor Ionotropic Kainate 3 (Grik3) was a target of miR-134-5p. The overexpression of miR-134-5p attenuated the hyperalgesic phenotype, excessive dendritic spine remodeling, excitatory synaptic structural plasticity, and Kainate receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in SDH resulting from remifentanil exposure. Besides, intrathecal injection of selective KA-R antagonist was able to reverse the GRIK3 membrane trafficking and relieved RIH. Conclusion: The miR-134-5p contributes to remifentanil-induced pronociceptive features via directly targeting Grik3 to modulate dendritic spine morphology and synaptic plasticity in spinal neurons.

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Section: Discussionsupporting

confidence: 74%

Spinal microRNA-134-5p targets glutamate receptor ionotropic kainate 3 to modulate opioid induced hyperalgesia in mice

et al. 2023

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“…Nrxs are evolutionarily conserved presynaptic CAMs encoded by three mammalian genes ( Nrx-1 , Nrx-2 , Nrx-3 ), each of which contains two promoters, leading to the generation of longer and shorter α-Nrx and β-Nrx pre-mRNAs, respectively. In mice, a third very short γ-isoform of Nrx-1 is produced via an additional internal promoter [ 7 ]. Structurally, α-Nrxs consist of six laminin/neurexin/sex-hormone (LNS) globular domains and three interspersed extracellular epidermal growth factor (EGF)-like repeats, with these alternating structures serving to tether proteins to the cell surface through a rigid and highly O-linked glycosylated stalk and a transmembrane domain.…”

Section: The Structural Characteristics Of Neurexins and Neuroliginsmentioning

confidence: 99%

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

Guo

Guan

et al. 2022

Cells

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Synapses serve as the interface for the transmission of information between neurons in the central nervous system. The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx–Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx–Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx–Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx–Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain.

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“…Recent biochemical and behavioral studies suggest a key role for the kainate receptor GluK2 in controlling abnormalities related to the behavioral symptoms of mania, such as psychomotor agitation, aggressiveness and hyperactivity [ 36 ], while the kainate receptor GluK3 was associated with recurrent major depressive disorder [ 37 ]. Kainate receptors are expressed in regions of spinal cord implied in the transmission of sensory stimulation and pain, and their functional dysregulation was linked to pain [ 38 , 39 ]. Several studies led to a variety of linkages between epilepsy and kainate receptors including different and sometimes contradictory mechanisms that clearly demonstrate the difficulty in studying kainate receptors in this respect [ 39 , 40 , 41 ].…”

Section: Willardiine and Its Analoguesmentioning

confidence: 99%

“…Kainate receptors are expressed in regions of spinal cord implied in the transmission of sensory stimulation and pain, and their functional dysregulation was linked to pain [ 38 , 39 ]. Several studies led to a variety of linkages between epilepsy and kainate receptors including different and sometimes contradictory mechanisms that clearly demonstrate the difficulty in studying kainate receptors in this respect [ 39 , 40 , 41 ].…”

Section: Willardiine and Its Analoguesmentioning

confidence: 99%

Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid

et al. 2022

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Willardiine is a nonprotein amino acid containing uracil, and thus classified as nucleobase amino acid or nucleoamino acid, that together with isowillardiine, forms the family of uracilylalanines isolated more than six decades ago in higher plants. Willardiine acts as a partial agonist of ionotropic glutamate receptors and more in particular it agonizes the non-N-methyl-D-aspartate (non-NMDA) receptors of L-glutamate: ie. the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate receptors. Several analogues and derivatives of willardiine have been synthesised in the laboratory in the last decades and these compounds show different binding affinities for the non-NMDA receptors. More in detail, the willardiine analogues have been employed not only in the investigation of the structure of AMPA and kainate receptors, but also to evaluate the effects of receptor activation in the various brain regions. Remarkably, there are a number of neurological diseases determined by alterations in glutamate signaling, and thus, ligands for AMPA and kainate receptors deserve attention as potential neurodrugs. In fact, similar to willardiine its analogues often act as agonists of AMPA and kainate receptors. A particular importance should be recognized to willardiine and its thymine-based analogue AlaT also in the peptide chemistry field. In fact, besides the naturally-occurring short nucleopeptides isolated from plant sources, there are different examples in which this class of nucleoamino acids was investigated for nucleopeptide development. The applications are various ranging from the realization of nucleopeptide/DNA chimeras for diagnostic applications, and nucleoamino acid derivatization of proteins for facilitating protein-nucleic acid interaction, to nucleopeptide-nucleopeptide molecular recognition for nanotechnological applications. All the above aspects on both chemistry and biotechnological applications of willardine/willardine-analogues and nucleopeptide will be reviewed in this work.

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The emerging role of kainate receptor functional dysregulation in pain

Cited by 3 publications

References 115 publications

Spinal microRNA-134-5p targets glutamate receptor ionotropic kainate 3 to modulate opioid induced hyperalgesia in mice

Spinal microRNA-134-5p targets glutamate receptor ionotropic kainate 3 to modulate opioid induced hyperalgesia in mice

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid

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