Involvement of calmodulin in neuronal cell death

A large body of evidence indicates that disturbances of Ca2+ homeostasis may be a causative factor in the neurotoxicity following cerebral ischemia. However, the mechanisms by which Ca2+ overload leads to neuronal cell death have not been fully elucidated. Calmodulin, a major intracellular Ca2+-binding protein found mainly in the central nervous system, mediates many physiological functions in response to changes in the intracellular Ca2+ concentration, whereas Ca2+ overload in neurons after excitotoxic insult may induce excessive activation of calmodulin signaling pathways, leading to neuronal cell death. To determine the role of calmodulin in the induction of neuronal cell death, we generated primary rat cortical neurons that express a mutant calmodulin with a defect in Ca2+-binding affinity. Neurons expressing the mutant had low responses of calmodulin-dependent signaling to membrane depolarization by high KCl and became resistant to glutamate-triggered excitotoxic neuronal cell death compared with the vector or wild-type calmodulin-transfected cells, indicating that blocking calmodulin function is protective against excitotoxic insult. These results suggest that calmodulin plays a crucial role in the processes of Ca2+-induced neuronal cell death and the possibility that the blockage of calmodulin attenuates brain injury after cerebral ischemia.