王以政博士简介

Neuronal signal transduction plays an important role in the regulation of neuronal activities. G-proteins and protein kinase cascades are key parts of the signal transduction. The ongoing research projects include the study of the mechanism and the consequence of activation of Gi by glutamate, the main excitatory neurotransmitter in the central nervous system, and the study of the potential role of PI-3 kinase and MAP (Mitogen-activated protein) kinase cascade in preventing/inducing neuronal apoptosis. A variety of methods of molecular biology, cellular biology and biochemistry are employed to investigate these problems, using primary neuronal cultures, cell lines, as well as animal model systems.
Under physiological conditions, glutamate mediates excitatory neurotransmission and synaptic plasticity, e.g., long-term potentiation/depression. However, overstimulation of glutamate receptors, particularly the NMDA and AMPA subtypes, is thought to contribute to a variety of pathological conditions, including epilepsy, stroke and various neurodegenerative diseases. The neurotoxicity, including necrosis or apoptosis, associated with NMDA and AMPA receptor overstimulation is likely to arise, at least in part, from the negative impact it has on cell signaling pathways normally associated with these receptors. Thus, a clearer understanding of the cellular signals triggered by the various glutamate receptors under normal and pathological conditions could lead to the identification of novel intracellular targets for future drug development. To this end, we have recently shown that, while both NMDA and AMPA stimulate p42 mitogen-activated protein (MAP) kinase in neurons, only AMPA-induced MAP kinase activity is inhibited by pertussis-toxin. Furthermore, AMPA stimulates MAP kinase via a novel mechanism in which the G-protein bg dimers released from a Gabg complex bind to a ras protein complex and cause a sequential activation of ras, raf kinase, MEK-1 and MAP kinase. This observation has led to our current study on the role of Gi-protein in the AMPA signaling. Another interest in our laboratory is to investigate the role of protein kinase cascade and ion homeostasis in apoptosis of neurons. A mechanism involving Bcl-2/Bax regulation and ion homeostasis was shown to account for the apoptotic process.