Calpain-mediated collapsin response mediator protein-1, -2, and -4 proteolysis after neurotoxic and traumatic brain injury.

Abstract

Collapsin response mediator proteins (CRMPs) are important molecules in neurite outgrowth and axonal guidance. Within the CRMP family, CRMP-2 has been implicated in several neurological diseases (Alzheimer's, epilepsy, and ischemia). Here, we investigated the integrity of CRMPs (CRMP-1, -2, -4, -5) after in vitro neurotoxin treatment and in vivo traumatic brain injury (TBI). After maitotoxin (MTX) and NMDA treatment of primary cortical neurons, a dramatic decrease of intact CRMP-1, -2 and -4 proteins were observed, accompanied by the appearance of distinct 55-kDa and 58-kDa breakdown products (BDP) for CRMP-2 and -4, respectively. Inhibition of calpain activation prevented NMDA-induced CRMP-2 proteolysis and redistribution of CRMP-2 from the neurites to the cell body, while attenuating neurite damage and neuronal cell injury. Similarly, CRMP-1, -2, and -4 were also found degraded in rat cortex and hippocampus following controlled cortical impact (CCI), an in vivo model of TBI. The appearance of the 55-kDa CRMP-2 BDP was observed to increase, in a time-dependent manner, between 24 and 48 h in the ipsilateral cortex, and by 48 hours in the hippocampus. The observed 55-kDa CRMP-2 BDP following TBI was reproduced by in vitro incubation of naive brain lysate with activated calpain-2, but not activated caspase-3. Sequence analysis revealed several possible cleavage sites near the C-terminus of CRMP-2. Collectively, this study demonstrated that CRMP-1, -2, and -4 are degraded following both acute traumatic and neurotoxic injury. Furthermore, calpain-2 was identified as the possible proteolytic mediator of CRMP-2 following excitotoxic injury and TBI, which appears to correlate well with neuronal cell injury and neurite damage. It is possible that the calpain-mediated truncation of CRMPs following TBI may be an inhibiting factor for post-injury neurite regeneration.

• Authors: Zhiqun Zhang, Andrew K Ottens, Shankar Sadasivan, Firas H Kobeissy, Tie Fang, Ronald L Hayes, Kevin K W Wang
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 24 Issue 3 Pg. 460-72 (Mar 2007) ISSN: 0897-7151 [Print] United States
• PMID: 17402852 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Dpysl3 protein, rat
• Dpysl5 protein, rat
• Excitatory Amino Acid Agonists
• Intercellular Signaling Peptides and Proteins
• Marine Toxins
• Nerve Tissue Proteins
• Oxocins
• Phosphoproteins
• collapsin response mediator protein-1
• collapsin response mediator protein-2
• N-Methylaspartate
• maitotoxin
• L-Lactate Dehydrogenase
• Calpain
• Caspase 3

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Brain (pathology)
• Brain Injuries (metabolism)
• Calpain (metabolism, physiology)
• Caspase 3 (metabolism)
• Cell Death
• Cells, Cultured
• Cerebral Cortex (metabolism, pathology)
• Electrophoresis, Polyacrylamide Gel
• Excitatory Amino Acid Agonists (toxicity)
• Hippocampus (metabolism, pathology)
• Immunoblotting
• Immunohistochemistry
• Intercellular Signaling Peptides and Proteins
• L-Lactate Dehydrogenase (metabolism)
• Marine Toxins (toxicity)
• N-Methylaspartate (toxicity)
• Nerve Tissue Proteins (metabolism)
• Neurons (metabolism, pathology)
• Neurotoxicity Syndromes (metabolism)
• Oxocins (toxicity)
• Phosphoproteins (metabolism)
• Rats
• Rats, Sprague-Dawley