ArticlePain2015
Protein kinase C gamma-mediated phosphorylation of GluA1 in the postsynaptic density of spinal dorsal horn neurons accompanies neuropathic pain, and dephosphorylation by calcineurin is associated with prolonged analgesia.
Article in Pain, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- The Wnt5a-PKCδ-GluA1 axis controls synapse-specific plasticity in HIV-1 gp120-induced pain pathogenesis.Brain : a journal of neurology · 2026Article
- Targeting Spinal Dorsal Horn Sensitisation in Chronic Pain: Mechanisms and Translational Strategies.Neuroscience bulletin · 2026Review
- The 5-HT Descending Facilitation System Contributes to the Disinhibition of Spinal PKCγ Neurons and Neuropathic Allodynia via 5-HTNeuroscience bulletin · 2025Article
- α2δ-1-Linked NMDA and AMPA Receptors in Neuropathic Pain and Gabapentinoid Action.Journal of neurochemistry · 2025Review
- Calcineurin and CK2 Reciprocally Regulate Synaptic AMPA Receptor Phenotypes via α2δ-1 in Spinal Excitatory Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Calcineurin regulates synaptic CaThe Journal of physiology · 2024Article
- Molecular Mechanisms of AMPA Receptor Trafficking in the Nervous System.International journal of molecular sciences · 2023Review
- Spinal AMPA receptors: Amenable players in central sensitization for chronic pain therapy?Channels (Austin, Tex.) · 2021Review
- Calcineurin Inhibition Causes α2δ-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- PKCγ promotes axonal remodeling in the cortico-spinal tract via GSK3β/β-catenin signaling after traumatic brain injury.Scientific reports · 2019Article
- Spinal PKCα inhibition and gene-silencing for pain relief: AMPAR trafficking at the synapses between primary afferents and sensory interneurons.Scientific reports · 2018Article
- PI3K/Akt Pathway is Required for Spinal Central Sensitization in Neuropathic Pain.Cellular and molecular neurobiology · 2018Article
- Changes in microRNA expression in the brachial plexus avulsion model of neuropathic pain.International journal of molecular medicine · 2018Article
- Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development.Current neuropharmacology · 2018Review
- Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis.International journal of molecular sciences · 2018Article
- Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced KThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases.Journal of aging research · 2016Review
- Intact subepidermal nerve fibers mediate mechanical hypersensitivity via the activation of protein kinase C gamma in spared nerve injury.Molecular pain · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Loss of calcineurin (protein phosphatase 3) activity and protein content in the postsynaptic density (PSD) of spinal dorsal horn neurons was associated with pain behavior after chronic constriction injury (CCI) of the rat sciatic nerve, and intrathecal administration of the phosphatase provided prolonged analgesia (Miletic et al. 2013). In this study, we examined whether one consequence of the loss of calcineurin was the persistent phosphorylation of the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPAR) receptors in the PSD. This would allow continual activation of AMPAR receptors at the synapse to help maintain a long-lasting enhancement of synaptic function, ie, neuropathic pain. We also investigated if the phosphorylation was mediated by protein kinase A (PKA), protein kinase C gamma (PKCγ), or calcium-calmodulin dependent kinase II (CaMKII), and if the prolonged calcineurin analgesia was associated with GluA1 dephosphorylation. Mechanical thresholds and thermal latencies were obtained before CCI. Seven days later, the behavioral testing was repeated before saline, calcineurin, or the specific peptide inhibitors of PKA (PKI-tide), PKCγ (PKC 19-31), or CaMKII (autocamtide-2-related inhibitory peptide) were injected intrathecally. The behavior was retested before the animals were euthanized and their PSD isolated. All CCI animals developed mechanical and thermal hypersensitivity. This was associated with phosphorylation of GluA1 in the ipsilateral PSD at Ser831 (but not Ser845) by PKCγ and not by PKA or CaMKII. Intrathecal treatment with calcineurin provided prolonged analgesia, and this was accompanied by GluA1 dephosphorylation. Therapy with calcineurin may prove useful in the prolonged clinical management of well-established neuropathic pain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.