Deciphering the role of c-Src tyrosine kinase in excitotoxic neuronal death during ischemic stroke
|Associate Professor Heung-Chin Chengfirstname.lastname@example.org||61-3-83442254||View page|
An ischemic stroke occurs when the one of the blood vessels supplying the brain (e.g. the middle cerebral artery) is blocked, causing damage to the adjacent neurons. The damaged neurons induce a second round of neuronal death by secreting an excessive quantity of the neurotransmitter glutamate.
Over-stimulation of glutamate receptors in the neighbouring viable neurons causes them to undergo cell death – a process known as excitotoxicity (Figure 1). Exactly how over-stimulation of glutamate receptors induces neuronal death is poorly understood.
Figure 1: Over-stimulation of glutamate receptors induces cell death of cultured primary cortical neurons. The viable neurons are stained with Calcein-AM (green) and the damaged neurons are stained with Ethidium homodimer-1 (red). To induce cell death, neurons were treated with 100 μM glutamate for 8 h.
Results of studies by ourselves and others have indicated that inhibitors of c-Src kinase are protectants, indicating that aberrant activation and/or subcellular localisation of c-Src contribute to excitotoxic neuronal death.
We are using cultured mouse primary cortical neurons and a rat model of ischemic stroke to decipher how c-Src is aberrantly activated in neurons undergoing excitotoxic neuronal death and how the activated c-Src induces premature death of neurons. We have demonstrated that c-Src is essential for neuronal survival under physiological condition. However, in neurons over-stimulated with glutamate, c-Src is aberrantly modified and activated. This aberrantly modified form of c-Src then directs neurons to undergo cell death. We are currently studying the structure and function of this aberrantly modified form of c-Src.
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