Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo

PLoS One. 2015 Apr 23;10(4):e0125119. doi: 10.1371/journal.pone.0125119. eCollection 2015.


The level of drebrin, an evolutionarily conserved f-actin-binding protein that regulates synaptic structure and function, is reduced in the brains of patients with chronic neurodegenerative diseases such as Alzheimer's disease (AD) and Down's syndrome (DS). It was suggested that excitotoxic neuronal death caused by overactivation of NMDA-type glutamate receptors (NMDARs) occurs in AD and DS; however, the relationship between excitotoxicity and drebrin loss is unknown. Here, we show that drebrin is a novel target of calpain-mediated proteolysis under excitotoxic conditions induced by the overactivation of NMDARs. In cultured rodent neurons, degradation of drebrin was confirmed by the detection of proteolytic fragments, as well as a reduction in the amount of full-length drebrin. Notably, the NMDA-induced degradation of drebrin in mature neurons occurred concomitantly with a loss of f-actin. Furthermore, pharmacological inhibition of f-actin loss facilitated the drebrin degradation, suggesting a functional linkage between f-actin and drebrin degradation. Biochemical analyses using purified drebrin and calpain revealed that calpain degraded drebrin directly in vitro. Furthermore, cerebral ischemia also induced the degradation of drebrin in vivo. These findings suggest that calpain-mediated degradation of drebrin is a fundamental pathology of neurodegenerative diseases mediated by excitotoxicity, regardless of whether they are acute or chronic. Drebrin regulates the synaptic clustering of NMDARs; therefore, degradation of drebrin under excitotoxic conditions may modulate NMDAR-mediated signal transductions, including pro-survival signaling. Overall, the results presented here provide novel insights into the molecular basis of cellular responses to excitotoxicity in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Calcium / metabolism
  • Calpain / metabolism*
  • Cells, Cultured
  • Excitatory Amino Acid Agonists / pharmacology*
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Humans
  • Mice
  • N-Methylaspartate / pharmacology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley


  • Actins
  • Excitatory Amino Acid Agonists
  • Neuropeptides
  • drebrins
  • N-Methylaspartate
  • Calpain
  • Calcium

Grant support

This work was supported by grant from Ministry of Education, Culture, Sports, Science and Technology, Japan [to TC and NY]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.