Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

Hanamura, Kenji; Washburn, Halley R.; Sheffler-Collins, Sean I.; Xia, Nan; Henderson, Nathan T; Tillu, Dipti V.; Hassler, Shayne; Spellman, Daniel S.; Zhang, Guoan; Neubert, Thomas A.; Price, Theodore J.; Dalva, Matthew B.

doi:10.1371/journal.pbio.2002457

Cited by 61 publications

(89 citation statements)

References 58 publications

(110 reference statements)

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“…Postsynaptic NMDARs turn over much more slowly, on the hour‐to‐day timescale (Lissin et al, ; Tovar & Westbrook, ; Groc et al, ). NMDAR clusters are 100–200 nm in diameter (Chen et al, ; Hanamura et al, ; Ladepeche et al, ).…”

Section: Postsynaptic Distribution Of Ampars and Nmdarsmentioning

confidence: 99%

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

2018

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The synapse transmits, processes, and stores data within its tiny space. Effective and specific signaling requires precise alignment of the relevant components. This review examines current insights into mechanisms of AMPAR and NMDAR localization by PSD‐95 and their spatial distribution at postsynaptic sites to illuminate the structural and functional framework of postsynaptic signaling. It subsequently delineates how β2 adrenergic receptor (β2 AR) signaling via adenylyl cyclase and the cAMP‐dependent protein kinase PKA is organized within nanodomains. Here, we discuss targeting of β2 AR, adenylyl cyclase, and PKA to defined signaling complexes at postsynaptic sites, i.e., AMPARs and the L‐type Ca2+ channel Cav1.2, and other subcellular surface localizations, the role of A kinase anchor proteins, the physiological relevance of the spatial restriction of corresponding signaling, and their interplay with signal transduction by the Ca2+‐ and calmodulin‐dependent kinase CaMKII. How localized and specific signaling by cAMP occurs is a central cellular question. The dendritic spine constitutes an ideal paradigm for elucidating the dimensions of spatially restricted signaling because of their small size and defined protein composition.

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Section: Postsynaptic Distribution Of Ampars and Nmdarsmentioning

confidence: 99%

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

2018

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“…The interaction between ephrins and Eph receptors leads to bidirectional signaling into Eph‐expressing cells (forward signaling) and ephrin‐expressing cells (reverse signaling) . In different chronic pain states, ephrin‐B2 ligand expressed by presynaptic sensory afferent fibers binds to EphB receptors distributed in the dorsal horn to mediate forward signaling . Additionally, this ligand‐receptor interaction further regulates the synaptic efficacy via communication with NMDA receptor .…”

Section: Introductionmentioning

confidence: 99%

“…In different chronic pain states, ephrin‐B2 ligand expressed by presynaptic sensory afferent fibers binds to EphB receptors distributed in the dorsal horn to mediate forward signaling . Additionally, this ligand‐receptor interaction further regulates the synaptic efficacy via communication with NMDA receptor . NMDA receptors can alter the calcium influx in the postsynaptic dorsal horn neuron and further transduce synaptic input into prolonged signals and contribute to neuronal plasticity in chronic pain models such as inflammatory, chronic constriction injury, bone cancer, and cross‐organ sensitization pain models …”

Section: Introductionmentioning

confidence: 99%

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

Theofanous

Florens

Appeltans

et al. 2020

Neurogastroenterology Motil

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Background Ephrin‐B2/EphB receptor signaling contributes to persistent pain states such as postinflammatory and neuropathic pain. Visceral hypersensitivity (VHS) is a major mechanism underlying abdominal pain in patients with irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) in remission, but the underlying pathophysiology remains unclear. Here, we evaluated the spinal ephrin‐B2/EphB pathway in VHS in 2 murine models of VHS, that is, postinflammatory TNBS colitis and maternal separation (MS). Methods Wild‐type (WT) mice and mice lacking ephrin‐B2 in Nav1.8 nociceptive neurons (cKO) were studied. VHS was induced by: 1. intracolonic instillation of TNBS or 2. water avoidance stress (WAS) in mice that underwent maternal separation (MS). VHS was assessed by quantifying the visceromotor response (VMRs) during colorectal distention. Colonic tissue and spinal cord were collected for histology, gene, and protein expression evaluation. Key Results In WT mice, but not cKO mice, TNBS induced VHS at day 14 after instillation, which returned to baseline perception from day 28 onwards. In MS WT mice, WAS induced VHS for up to 4 weeks. In cKO however, visceral pain perception returned to basal level by week 4. The development of VHS in WT mice was associated with significant upregulation of spinal ephrin‐B2 and EphB1 mRNA expression or protein levels in the TNBS model and upregulation of spinal ephrin‐B2 protein in the MS model. No changes were observed in cKO mice. VHS was not associated with persistent intestinal inflammation. Conclusions and Inferences Overall, our data indicate that the ephrin‐B2/EphB1 spinal signaling pathway is involved in VHS and may represent a novel therapeutic target.

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“…N-methyl-D-aspartate (NMDA) receptors are relevant to chronic neuropathic pain, injury-induced pain behaviour and persistent pain of spinal lamina II neurons [10][11][12][13]. The NMDA receptor 2B subunit (N R 2B) shows a relatively restricted distribution in pathways of nociceptive transmission [14].…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

β-Elemene alleviates bone cancer-related pain in rats by modulating N-methyl-D-aspartate receptor 2B subunit

Gong¹,

Cai²,

Zhou³

et al. 2018

Trop. J. Pharm Res

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Purpose: To investigate the effect of β-elemene on bone cancer-related pain (BCRP) and its underlying mechanism in a rat model. Methods: A rat model of BCRP was established by injection of Walker 256 cells into the medullary cavity in adult male Sprague-Dawley rats. The effects of β-elemene on pain-related behaviours were assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to analyse the transcription and translation levels of N-methyl-D-aspartate receptor 2B subunit (NR2B), respectively. Results: This study found that PWMT and PWTL were significantly decreased in rats as evidence of successful establishment of a rat model of BCRP. Behavioral test showed that β-elemene treatment could attenuate pain-related behaviours. This analgesic effect began 1 h after drug injection, reached the highest value at 2 h, declined at 4 h, and disappeared by 24 h. qRT-PCR and western blotting indicated that intrathecal administration of β-elemene down-regulated mRNA and protein levels of NR2B. Conclusion: The results show that β-elemene alleviates behaviours related to pain in a rat model of BCRP probably by modulating NR2B, thus indicating a new potential treatment method for cancerrelated pain.Keywords: β-Elemene, Bone cancer, Pain relief,, Sensitisation This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest

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Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

Cited by 61 publications

References 58 publications

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

β-Elemene alleviates bone cancer-related pain in rats by modulating N-methyl-D-aspartate receptor 2B subunit

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Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

Cited by 61 publications

References 58 publications

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

β-Elemene alleviates bone cancer-related pain in rats by modulating N-methyl-D-aspartate receptor 2B subunit

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Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling