|Budget Amount *help
¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1996 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1995 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Synaptic stimulation activates specific program of gene expression in the nucleus of postsynaptic neurons, which seems critical to long-term adaptive responses of neuronal cells. It has been thought that MAP kinase has an important role in transducing signals that are initiated by neurotransmitter release. Calcium influx through L-type calcium channels activates MAP kinase, and L-type calcium channels and MAP kinase are localized to postsynaptic structures in central nervous system. To elucidate the possibility that anesthetics affect the synaptic plasticity, I examined the effects of anesthetics on depolarization-induced MAP kinase activation and cFos expression in PC12 cells.
1.Outgrowth of neurofilaments induced by nerve growth factor was not affected by 30muM dibucaine or 200 muM tetracaine. PC12 cells died in the presence of higher concentrations of these local anesthetics
2.Dibucaine, tetracaine and propofol dose-dependently inhibited KC1-induced cFos expression in the nucleus. cFo
s expression induced by 50 mM KC1 was suppressed by dibucain, tetracaine, and propofol at the concentrations of 30,50 and 50 muM,respectively. KC1-induced cFos expression was blocked by 3 mM EDTA,10 muM nifedipine but not by 3 muM omega-conotoxin, indicating that KC1-induced cFos expression depends on calcium influx through L-type calcium channels. The concentrations of dibucaine and tetracaine which blocked cFos expression were compatible with those which were reported to inhibit L-type calcium channels in spinal cord ganglion cells. KC1-induced cFos exppression was also inhibited by PD9805, a MEK (MAP kinase kinase) inhibitor.
3.Dibucaine and tetracaine inhibited KC1-induced MAP kinase activation in dose-dependent manner. KC1-induced MAP kinase activation was suppressed by 10 muM dibucaine and 50 muM tetracaine.
These findings suggest that dibucaine and tetracaine suppress L-type calcium channels and MAP kinase signaling pathway, resulting inhibition of gene expression in the nucleus of neuronal cells. It is supposed that propofol has the same effect on MAP signaling pathway and gene expression.
Now, I examine the effects of anesthetics on MAP kinase signaling pathway in human neutrophils.