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.