河豚毒素TTX 的药用前景.ppt

TTX 的药用前景 SWIBC 王秀敏 药理学作用 在生物学及医学领域内，TTX主要作为工具药，广泛应用于神经、肌肉、浦氏纤维及其它组织的实验研究 对Na+离子通道的阻断作用 Na+离子通道的结构 TTx阻断心肌 Na+通道的作用具有电压依赖性(voltage—dependent)和使用依赖性(use．dependent)两种特征 TTX 对骨骼肌的作用主要是通过神经肌肉接头的阻断，同时对骨骼肌也有直接抑制作用。 The diagram above depicts a sodium channel with four repeating units. It is thought each domain folds into six transmembrane helices. The orange filled circles on the connecting segments between S5 and S6 represents a TTX binding site. An inactivation gate (IG) exists between domains III and IV. Voltage gated sodium channels consist of an α-subunit responsible for selectivity and voltage gating. Tetrodotoxin, much larger than the sodium ion, acts like a cork in a bottle, preventing the flow of sodium until it slowly diffuses off. A mortal dose of tetrodotoxin is but a single milligram. Tetrodotoxin competes with the hydrated sodium cation and enters the Na+-channel where it binds. It is proposed that this binding results from the interaction of the positively charged guanidino group on the tetrodotoxin and negatively charged carboxylate groups on side chains in the mouth of the channel. Saxitoxin, a natural product from dinoflagellates, acts in a similar way and is also a potent nerve poison. a victim of TTX poisoning will still be conscious.? This is caused by site specific binding of TTX to voltage gated sodium ion channels in the nervous tissues There are two types of these ion channels--those with high affinity for TTX and those with low affinity for TTX.? Those with low affinity are primarily in cardiac tissue while ion channels with high affinity for TTX are distributed throughout the rest of the body.? Based on this information it can be expected that cardiac arrhythmia would result from higher doses. A secondary effect of this toxicity is the inability of brain cells to receive oxygen properly resulting in a lightheaded feeling and overall weakness TTX的药理作用 TTX是带胍基的水溶性分子，带正电荷的胍基部分伸人到钠通道的狭窄部分—— 选择性滤孔，与通道壁的游离羧基相结合，毒素分子的其它部分则堵塞了通道，从而阻断