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首页> 外文期刊>Neuropharmacology >Therapeutic effectiveness of botulinum neurotoxin A: Potent blockade of autonomic transmission by targeted cleavage of only the pertinent SNAP-25
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Therapeutic effectiveness of botulinum neurotoxin A: Potent blockade of autonomic transmission by targeted cleavage of only the pertinent SNAP-25

机译：肉毒杆菌神经毒素A的治疗效果：仅靶向切割相关SNAP-25即可有效阻断自主神经传播

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摘要

In search of a basis for the impressive potency of an endoprotease that cleaves SNAP-25, botulinum neurotoxin type A (BoNT/A), in treating numerous diseases due to hyper-active autonomic nerves, truncation of its target and inhibition of neurotransmission were studied in rat sympathetic neurons. Tetrodotoxin-sensitive spontaneous cholinergic neurotransmission was blocked 80% by 1 pM BoNT/A despite cleaving 20% of the SNAP-25. A maximum cleavage of ～60% SNAP-25 could be achieved with 1 nM BoNT/A, despite an absence of non-cleavable SNAP-25 in the detergent-solubilised neurons. In contrast, BoNT/E (100 nM) truncated nearly all the SNAP-25 in the intact cells, but was unable to block neurotransmission at low concentrations like BoNT/A. Chimeras created by inserting the acceptor-binding HC domain of BoNT/A into BoNT/E still cleaved all the SNAP-25, indicating ubiquitous expression of BoNT/A acceptors. Accordingly, SV2 and SNAP-25 were found to be co-expressed and broadly co-localised in neurons, but absent from non-neuronal cells. On the other hand, partial cleavage by the BoNT/A protease persisted upon replacing its HC with counterparts from BoNT/E or BoNT/B. Moreover, limited cleavage of SNAP-25 was conferred onto the protease from BoNT/E when fused to the N-terminus of BoNT/A. Thus, the BoNT/A protease is uniquely well-adapted for selectively inactivating the SNAP-25 directly involved in neurotransmission; this together with the toxin's acceptor and its target being localised on the peri-somatic boutons likely contribute to its exceptional therapeutic utility in the clinic.
机译：为了寻找能裂解SNAP-25（A型肉毒杆菌神经毒素，BoNT / A）的内切蛋白酶在治疗由于自主神经过度活跃而引起的多种疾病，其靶标被截断和抑制神经传递方面令人印象深刻的功效的基础，在大鼠交感神经元中1pM BoNT / A对河豚毒素敏感的自发性胆碱能神经传递的阻滞作用> 80％，尽管裂解SNAP-25的作用<20％。尽管在去污剂溶解的神经元中不存在不可裂解的SNAP-25，但> 1 nM BoNT / A时，最大裂解可达SNAP-25的约60％。相比之下，BoNT / E（100 nM）截短了完整细胞中几乎所有的SNAP-25，但无法像BoNT / A那样在低浓度下阻断神经传递。通过将BoNT / A的受体结合HC结构域插入BoNT / E中而产生的嵌合体仍然切割了所有SNAP-25，表明BoNT / A受体的普遍表达。因此，发现SV2和SNAP-25在神经元中共表达并广泛共定位，但非神经元细胞中不存在。另一方面，当用来自BoNT / E或BoNT / B的对应物替换其HC时，BoNT / A蛋白酶的部分切割仍然存在。而且，当融合到BoNT / A的N末端时，SNAP-25的有限切割被赋予来自BoNT / E的蛋白酶。因此，BoNT / A蛋白酶具有独特的适应性，可以选择性地使直接参与神经传递的SNAP-25失活。这与毒素的受体及其靶标定位在体细胞周围的按钮上有关，可能有助于其在临床上的卓越治疗作用。

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