A novel alpha-conopeptide Eu1.6 inhibits N-type (Ca(V)2.2) calcium channels and exhibits potent analgesic activity

作者：Liu, Zhuguo; Bartels, Peter; Sadeghi, Mahsa; Du, Tianpeng; Dai, Qing; Zhu, Cui; Yu, Shuo; Wang, Shuo; Dong, Mingxin; Sun, Ting; Guo, Jiabin; Peng, Shuangqing; Jiang, Ling^*; Adams, David J.^*; Dai, Qiuyun^*

来源：Scientific Reports, 2018, 8(1): 1004.

DOI：10.1038/s41598-017-18479-4

• NICOTINIC ACETYLCHOLINE-RECEPTORS
• NACHR ALPHA-3-BETA-2
• OMEGA-CONOTOXINS
• CONUS-MARMOREUS
• PAIN
• DIVERSITY
• RAT
• ALPHA-9-ALPHA-10
• ACTIVATION
• ZICONOTIDE

We here describe a novel alpha-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong antin-ociceptive activity by an unexpected mechanism of action. Unlike other alpha-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the alpha 3 beta 4 and alpha 7 nAChR subtypes and TTX-resistant sodium channels, and no activity at TTX-sensitive sodium channels in rat dorsal root ganglion (DRG) neurons, or opiate receptors, VR1, KCNQ1, L-and T-type calcium channels expressed in HEK293 cells. However, Eu1.6 inhibited high voltage-activated N-type calcium channel currents in isolated mouse DRG neurons which was independent of GABA(B) receptor activation. In HEK293 cells expressing Ca(V)2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba2+ currents in a voltage-and state-dependent manner. Inhibition of Ca(V)2.2 by Eu1.6 was concentration-dependent (IC50 - 1 nM). Significantly, systemic administration of Eu1.6 at doses of 2.5-5.0 mu g/kg exhibited potent analgesic activities in rat partial sciatic nerve injury and chronic constriction injury pain models. Furthermore, Eu1.6 had no significant side-effect on spontaneous locomotor activity, cardiac and respiratory function, and drug dependence in mice. These findings suggest alpha-conopeptide Eu1.6 is a potent analgesic for the treatment of neuropathic and chronic pain and opens a novel option for future analgesic drug design.

• 出版日期2018-1-17
• 单位中国科学院; 波谱与原子分子物理国家重点实验室