Ion channel modulation as the basis for neuroprotective action of MS-153
Ion channel modulation as the basis for neuroprotective action of MS-153
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DOI：
10.1111/j.1749-6632.1999.tb08018.x
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Narahashi, T
中科院分区：
文献类型：
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作者：
Uenishi, H;Huang, CS;Narahashi, T
MS-153，(R)-(-)-5-甲基-1-烟酰基-2-吡唑啉是一种新的神经保护药物，最近的文献数据表明，它可以抑制缺血时谷氨酸的积聚和蛋白激酶C-γ(PKC-γ)的移位。本研究旨在证明MS-153阻断参与谷氨酸积累的神经受体和离子通道的假说。分离大鼠背根神经节和额叶皮质神经元，采用全细胞膜片钳技术记录通道电流。观察了浸浴MS-153对背根神经节神经元河豚毒素敏感和抗河豚毒素钠通道、高电压门控钙通道以及谷氨酸、N-甲基-D-天冬氨酸(NMDA)、红藻氨酸、α-氨基-3-羟基-5甲基-4-异恶酚丙酸(AMPA)、γ-氨基丁酸(GABA)和乙酰胆碱(ACh)激活通道的影响。MS-153在300mU浓度下对河豚毒素敏感和抗河豚毒素钠通道无影响。1-300 mU MS-153可抑制或不影响高电压门控钙通道。MS-153的可变阻断作用是由于单个神经元内细胞内成分的活性不同，特别是PKC的活性，已知其易位被MS-153抑制。当100 nM佛波酯(PMA)作用于神经元时，MS-153能更频繁地抑制钙通道电流。通过记录膜片移液管细胞内应用特异性PKC抑制剂Calphostin C(0.5mM)，可完全取消MS-153对钙通道电流的抑制。MS-153在300 mM时不影响谷氨酸、NMDA、海人藻酸、AMPA、GABA和ACh诱发的电流。结论：MS-153通过与PKC相互作用抑制高电压门控性钙通道，从而阻止神经末梢谷氨酸的大量释放。
MS-153, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline is a new neuroprotective drug, Recent data in the literature suggest that it inhibits glutamate accumulation occurring during ischemia and the translocation of protein kinase C gamma (PKC gamma). The present study was undertaken to prove the hypothesis that MS-153 blocks neuroreceptors and ion channels involved in glutamate accumulation. Neurons isolated from rat dorsal root ganglia and frontal cortex were used for recording channel currents by the whole-cell patch clamp technique. The effects of bath-applied MS-153 were examined on: tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels and high voltage-gated calcium channels of dorsal root ganglion neurons, and channels activated by glutamate, N-methyl-D-aspartate (NMDA), kainate, alpha-amino-3-hydroxy-5methyl- 4-isoxarole propionic acid (AMPA), gamma-aminobutyric acid (GABA) and acetylcholine (ACh) in cortical neurons.MS-153 at a concentration of 300 mu M had no effect on either:tetrodotoxin-sensitive or tetrodotoxin-resistant sodium channels. High voltage-gated calcium channels were either suppressed or not affected by 1-300 mu M MS-153. The variable blocking effect of MS-153 was due to the variable activity of intracellular components in individual neurons, especially that of PKC, whose translocation is known to be inhibited by MS-153. When 100 nM phorbol 12-myristate-13-acetate (PMA) was applied to neurons, MS-153 suppressed the calcium channel current more frequently. Calphostin C (0.5 mu M), a specific PKC inhibitor, applied intracellularly via recording patch pipette, completely abolished MS-153 suppression of the calcium channel current. Currents induced by glutamate, NMDA, kainate, AMPA, GABA or ACh were not affected by MS-153 at 300 mu M. It was concluded that MS-153 inhibited high voltage-gated calcium channels through interactions with PKC, thereby preventing massive release of glutamate from nerve terminals in ischemic conditions.