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Phosphoproteomics Uncovers a Neuroimmune Perspective on Trigeminal Neuralgia: Sexually Dimorphic Regulatory Networks Linking Calcium Channels to the Complement Cascade

ABSTRACT: Background: Trigeminal neuralgia (TN) is a debilitating neuropathic pain disorder with a higher prevalence in females, yet its pathogenic mechanisms and underlying sexual dimorphism remain incompletely understood. Phosphorylation modifications are critical regulators of pain signaling, but comprehensive phosphoproteomic profiling of TN has not been reported. Methods: We established a chronic constriction injury model of the infraorbital nerve (ION-CCI) in male and female rats via an intraoral approach. Mechanical allodynia was behaviorally confirmed. Integrated proteomic and phosphoproteomic analyses of trigeminal ganglia were performed at postoperative day 7 using data-independent acquisition mass spectrometry. Bioinformatic analyses included pathway enrichment, kinase-substrate prediction, and drug target annotation. Results: Key findings include: (1) Proteomics identified 5,820 proteins and phosphoproteomics revealed 8,830 phosphopeptides mapping to 8,139 phosphoproteins; (2) Complement component C1qa was upregulated in both sexes, while kininogen (KNG1/2) showed female-specific elevation; (3) MAPK pathway activation was prominent, with significantly increased HSPB1 phosphorylation at S86, predicted to be regulated by MAPKAPK2/3; (4) N-type calcium channel (CACN1B) phosphorylation was enhanced in both sexes, suggesting a CACN1B-MAPK-HSPB1 signaling axis; (5) Drug annotation identified Ziconotide (CACN1B blocker) as a therapeutic candidate. Conclusions: This study reveals a neuroimmune phosphorylation network in TN pathogenesis, establishing complement activation and the CACN1B-MAPK-HSPB1 axis as central mechanisms. Sexually dimorphic expression of complement and kinin components provides molecular insights into TN's female predominance. These findings offer therapeutic targets and support sex-specific immunomodulatory strategies for TN.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Trigeminal Ganglion

DISEASE(S): Trigeminal Neuralgia

SUBMITTER: xiaojie zhai

LAB HEAD: Xiaojie Zhai

PROVIDER: PXD066745 | Pride | 2026-02-26

REPOSITORIES: Pride

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			Action	DRS
	Results.zip	Other
	XB00046B1DA_CION1_F_Slot1-23_1_2339.d.zip	Other
	XB00046B1DA_CION1_M_Slot1-17_1_2331.d.zip	Other
	checksum.txt	Txt

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Project description:Cis-9, trans-11-conjugated linoleic acid (c9, t11-CLA), a functional fatty acid, is one of the research hotspots in the fields of functional dairy products development because of its multiple beneficial effects in humans and animals. In milk, most c9, t11-CLA is de novo synthesized from trans-11-octadecenoic acid (TVA) and it is confirmed that genes such as stearoyl-coA desaturase 1 (SCD1) play a key role in the synthesis. However, few studies have been reported to deeply elucidate the SCD1-dependent molecular mechanism of cis9, trans11-CLA synthesis and its relationship with the pathways of energy metabolism and lipid metabolism. Therefore, in the present study, MAC-T cells were divided into three groups: CAY group (SCD1-inhibited MAC-T cell model with the addition of CAY, TVA), TVA group (only TVA), and Control group (without CAY, TVA). The relative mRNA expression of SCD1 was measured using real-time PCR, while TVA accumulation and c9, t11 -CLA synthesis were analyzed using gas chromatography (GC). The SCD1-related proteins were firstly screened in MAC-T cells by Tandem Mass Tag (TMT)-based quantitative proteomics analysis, then their functions were annotated by bioinformatic analysis, and finally their relationships with SCD1 were evaluated by parallel reaction monitoring (PRM) analysis and small RNA interference. The results showed that the deficiency of SCD1 led by CAY10566 blocked the synthesis of c9, t11-CLA in MAC-T cells. Sixty-one SCD1-associated proteins were screened and found to be mainly involved in the pathways of energy metabolism and lipid metabolism, such as glycolytic pathway, pentose phosphate pathway, fatty acid elongation pathway, and unsaturated fatty acid biosynthesis. Among these genes, 17 proteins were validated under the PRM analysis. PGAM1 (phosphoglycerate mutase 1), TPI1 (triosephosphate isomerase 1), LDHB (lactate dehydrogenase B), and ALDOA (aldolase, fructose-bisphosphate A) were verified to have a negative relationships with SCD1. This study furthered our understanding of the molecular mechanisms of c9, t11-CLA synthesis in the mammary glands of dairy cows.

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Phosphoproteomics Uncovers a Neuroimmune Perspective on Trigeminal Neuralgia: Sexually Dimorphic Regulatory Networks Linking Calcium Channels to the Complement Cascade

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