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Multi-Omics Analysis Reveals Nono-Kcnq2 Regulation of Neuronal Excitability in Neuropathic Pain [scRNA-Seq]

ABSTRACT: Neuropathic pain imposes a profound, multidimensional burden on patients, largely due to limited therapeutic options stemming from inadequately understood pathomechanisms. In this study, we employed an integrated multi-omics approach to identify a novel Nono–KCNQ2 regulatory axis that underpins pain progression in chronic constriction injury (CCI) models. Proteomic analysis revealed a marked reduction in potassium ion channel protein expression accompanied by aberrant glutamatergic neuron activation during neuropathic pain progression. Additionally, phosphoproteomic profiling demonstrated that impaired phosphorylation of these channels—most notably KCNQ2—reduces ion permeability and promotes neuronal hyperexcitability. catTFRE analysis further indicated that diminished Nono transcription factor activity is associated with the downregulation of potassium ion channels in CCI rats. Moreover, single-cell RNA sequencing and spatial transcriptomics localized the co-expression of Nono and Kcnq2 to specific neuronal populations, namely Prph⁺ ventral horn and Nrxn3⁺ dorsal horn neurons, findings that were corroborated by immunofluorescence assays. Critically, CCI-induced Nono dysfunction within these subpopulations precipitates deficits in KCNQ2 signaling, ultimately leading to glutamatergic overactivation and enhanced pain sensitivity. Collectively, our findings underscore the pivotal role of ion channel transcriptional regulation in pain chronification and suggest that targeted modulation of Nono, coupled with pharmacological activation of KCNQ2, may represent a promising therapeutic strategy for neuropathic pain.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE304729 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:The pathogenesis of neuropathic pain is complex, and effective treatment methods are lacking in clinical practice. Recent studies have shown that glucose metabolism reprogramming may be involved in the process of neuropathic pain, but its role and molecular regulatory mechanisms in neuropathic pain are still unclear. In this study, a rat model of chronic constriction injury of the sciatic nerve (CCI) was established, and the pain threshold was evaluated through behavioural analysis. Morphological staining, transmission electron microscopy, transcriptome sequencing, Western blotting, immunofluorescence staining, ELISA, and the whole-cell patch clamp technique were used to systematically observe neuropathological changes, identify differentially expressed genes and associated pathways, and measure the expression levels of glycolysis-related indicators and the key regulatory factor fibroblast growth factor 4 (FGF4). The results showed that the pain threshold of rats decreased and that the structure of sciatic nerve tissue was damaged after CCI. Transcriptome sequencing of the sciatic nerve showed a significant increase in the expression levels of glycolysis-related indicators. Subsequent experiments confirmed that FGF4 expression was downregulated in the sciatic nerve and spinal dorsal horn after CCI, whereas the expression of hypoxia-inducible factor-1α (HIF-1α) and its key downstream glycolytic enzymes was upregulated, accompanied by increased levels of lactic acid and proinflammatory cytokines and decreased ATP levels. The spinal dorsal horn exhibited both synaptic structural abnormalities and neuronal hyperexcitability. Inhibiting HIF-1α alleviated pain and suppressed glycolysis, whereas the overexpression of FGF4 specifically reversed the increase in HIF-1α expression, inhibited neuronal glycolysis, and reduced neuroinflammation and central sensitization, ultimately effectively relieving pain. This study reveals the core role of the FGF4/HIF-1α-mediated regulation of neuronal glycolysis in neuropathic pain, providing a new theoretical basis and experimental evidence for a deeper understanding of the metabolic mechanism of neuropathic pain and the development of targeted treatment strategies.

Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].

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Multi-Omics Analysis Reveals Nono-Kcnq2 Regulation of Neuronal Excitability in Neuropathic Pain [scRNA-Seq]

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