A novel μ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors
A novel μ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors
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DOI：
10.1111/j.1476-5381.2012.01837.x
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发表时间：
2012-07-01
影响因子：
7.3
通讯作者：
Molgo, Jordi
中科院分区：
文献类型：
--
作者：
Favreau, Philippe;Benoit, Evelyne;Molgo, Jordi
背景和目的：魔芋多肽家族的定义是其阻断电压门控钠通道(VGSCs)的能力，这一特性可用于开发肌松剂和止痛药。我们在一系列制剂和分子靶点上表征了一种新的粘蛋白多肽(MU-CnIIIC)的药理作用，以评估其作为肌松药的潜力。实验方法：测定并合成Mu-CnIIIC，其特征是直接阻断小鼠骨骼肌的抽动张力，以及小鼠坐骨神经和狗狗嗅神经的动作电位。MU-CnIIIC还在表达各种啮齿动物VGSC的HEK-293细胞上以及电压门控钾通道和烟碱型乙酰胆碱受体(NAChRs)上进行了研究，以评估交叉相互作用。对结构数据进行了核磁共振实验。结果与Mu-SIIIA、Mu-SmIIIA和Mu-PIIIA相比，合成Mu-CnIIIC可降低小鼠半横肌的收缩张力(IC50=150 nM)，对小鼠指长伸肌(IC=46 nM)有较高的阻断作用。MU-CnIIIC长时间阻断NaV1.4(IC50=1.3 nM)和NaV1.2通道。心脏NaV1.5和DRG特异的NaV1.8通道在1MU时不被阻断。MU-CnIIIC还阻断A3β2 nAChR亚型(IC50=450 nM)，对A7和A4β2亚型的阻断程度较小。对Mu-CnIIIC的结构测定表明，它与作用于nAChRs的α-芋螺毒素有一些相似之处。结论：Mu-CnIIIC能有效阻断骨骼肌和神经中的VGSCs，适用于肌松作用。其非典型的药理学特征提示了VGSCs和nAChR通道之间的一些共同的结构特征。
BACKGROUND AND PURPOSE The mu-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new mu-conopeptide (mu-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant. EXPERIMENTAL APPROACH mu-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. mu-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data. KEY RESULTS Synthetic mu-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC50= 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with mu-SIIIA, mu-SmIIIA and mu-PIIIA. mu-CnIIIC blocked NaV1.4 (IC50= 1.3 nM) and NaV1.2 channels in a long-lasting manner. Cardiac NaV1.5 and DRG-specific NaV1.8 channels were not blocked at 1 mu M. mu-CnIIIC also blocked the a3 beta 2 nAChR subtype (IC50= 450 nM) and, to a lesser extent, on the a7 and a4 beta 2 subtypes. Structure determination of mu-CnIIIC revealed some similarities to a-conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS mu-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels.