2. Academic Validation
  3. Collapsin response mediator protein 2 modulates synaptic function by stabilizing the surface expression of phosphorylated AMPA receptor GluA2 subunits

Collapsin response mediator protein 2 modulates synaptic function by stabilizing the surface expression of phosphorylated AMPA receptor GluA2 subunits

  • Brain Res. 2025 Sep 15:1863:149798. doi: 10.1016/j.brainres.2025.149798.
JiaMing Wu 1,  Bingyu Ren 2,  Yichen Yin 3,  LongFei Cheng 4,  Jiong Li 5,  Keen Chen 6,  Guoqing Guo 7,  Jifeng Zhang 8
Affiliations

Affiliations

  • 1 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China; Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: wujiaming0013@163.com.
  • 2 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China. Electronic address: bingyuren@jnu.edu.cn.
  • 3 Department of Neurology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510235, China. Electronic address: yychen2002@163.com.
  • 4 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China; Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: cheng11055@qq.com.
  • 5 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China. Electronic address: jiongli2014@jnu.edu.cn.
  • 6 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China; Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: tcken@jnu.edu.cn.
  • 7 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China. Electronic address: tgqguo@jnu.edu.cn.
  • 8 Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou 510630, China. Electronic address: tzjf_jennifer@jnu.edu.cn.
PMID: 40618868 DOI: 10.1016/j.brainres.2025.149798
Abstract

The Collapsin response mediator protein 2 (CRMP2) is one of the most studied members of the CRMPs family, well-documented for its involvement in neurite extension and dendritic spine development. While our previous studies demonstrated CRMP2's role in regulating the surface expression of the AMPAR GluA1 subunit, its potential regulatory effects on GluA2, the calcium-impermeable AMPAR subunit, remain unexplored. In this study, we discovered that CRMP2 interacted with wild-type GluA2, increased the surface expression of GluA2, and enhanced the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs). Upon phorbol myristate acetate (TPA) induced activation of protein kinase C (PKC), the surface expression of GluA2 decreased significantly, as phosphorylation of GluA2 at the S880 site is known to promote its internalization. However, CRMP2 overexpression stabilized GluA2 surface expression during PKC activation or overexpression. Co-immunoprecipitation using point mutations that mimic or prevent GluA2 S880 phosphorylation revealed that phosphorylation promoted the binding between CRMP2 and GluA2. Furthermore, CRMP2 knockdown by siRNA reduced the amplitude and frequency of PKCζ-induced mEPSCs. Collectively, our findings reveal a role for CRMP2 in AMPAR trafficking, where it stabilizes surface-expressed GluA2 in both its unphosphorylated and phosphorylated forms.

Keywords

AMPARs trafficking; CRMP2; GluA2 subunit; Phosphorylation.

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