2. Academic Validation
  3. Caveolin-1 negatively regulates the calcitonin receptor-like receptor and neuroinflammation in a female mouse model of migraine

Caveolin-1 negatively regulates the calcitonin receptor-like receptor and neuroinflammation in a female mouse model of migraine

  • J Neuroinflammation. 2025 May 21;22(1):134. doi: 10.1186/s12974-025-03466-8.
Yanjie Zhou # 1,  Wu Chen # 2,  Yu Zhang 1,  Liu Yang 1 3,  Fu Lu 1,  Wen Yan 1,  Qingfang Xie 1,  Ying Huang 1,  Wanbin Huang 1,  Lintao Wang 1,  Ziming Zeng 1,  Zheman Xiao 4
Affiliations

Affiliations

  • 1 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
  • 2 Department of Urology, Renmin Hospital of Wuhan University, Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
  • 3 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
  • 4 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China. zmxiao@whu.edu.cn.
  • # Contributed equally.
PMID: 40399967 DOI: 10.1186/s12974-025-03466-8
Abstract

Background: Caveolin-1 (CAV1), a scaffolding protein critical for caveolae formation, regulates G-protein-coupled receptor (GPCR) signaling via caveolae-mediated endocytosis. The Calcitonin receptor-like receptor (CLR), a GPCR and core subunit of the Calcitonin gene-related peptide (CGRP) receptor, is a therapeutic target for migraine. However, the role of CAV1 in CLR regulation and migraine remains unclear.

Methods: A migraine model was established in female mice via dural inflammatory soup (IS) application. Migraine-like behaviors were assessed using Von Frey filament, spontaneous pain behavior counts, light/dark box, and acetone test. CAV1 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. Methyl-β-cyclodextrin (MβCD) was used to inhibit caveolae-mediated endocytosis. The molecular mechanism of CAV1 on CLR and neuroinflammation was investigated using biochemistry, multiplex immunohistochemistry staining, internalization assay, and co-immunoprecipitation.

Results: Repeated IS stimulation elevated CLR expression and internalization in the trigeminal nucleus caudalis (TNC), concurrently activating ERK/CREB signaling, promoting microglial activation, and increasing inflammatory cytokines (TNFα, IL-1β). CAV1 directly interacted with CLR, promoting its degradation. CAV1 knockdown in the TNC exacerbated migraine pathology, characterized by CLR accumulation, enhanced ERK/CREB phosphorylation, and amplified neuroinflammation. Conversely, CAV1 overexpression or MβCD-mediated caveolae disruption normalized CLR levels, reduced signaling hyperactivity, and reversed nociceptive behaviors.

Conclusion: CAV1 negatively regulates CLR stability, suppressing ERK/CREB signaling and microglial inflammation in a preclinical female migraine model. These findings suggest that CAV1 contributes to migraine-related hyperalgesia and may represent a novel therapeutic target for migraine treatment.

Keywords

CLR; Caveolin-1; Microglia; Migraine; Neuroinflammation.

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