A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity

Sci Rep. 2018 Jan 17;8(1):1004. doi: 10.1038/s41598-017-18479-4.

Zhuguo Liu ¹, Peter Bartels ², Mahsa Sadeghi ² ³, Tianpeng Du ⁴, Qing Dai ¹, Cui Zhu ¹, Shuo Yu ¹, Shuo Wang ¹, Mingxin Dong ¹, Ting Sun ¹, Jiabin Guo ⁵, Shuangqing Peng ⁵, Ling Jiang ⁶, David J Adams ⁷ ⁸, Qiuyun Dai ⁹

Affiliations

1 Beijing Institute of Biotechnology, Beijing, 100071, China.
2 Health Innovations Research Institute, RMIT University, Melbourne, Victoria, 3083, Australia.
3 Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia.
4 Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Science, Wuhan, 430071, China.
5 Institute for Disease control and Prevention, Beijing, 100071, China.
6 Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Science, Wuhan, 430071, China. [email protected].
7 Health Innovations Research Institute, RMIT University, Melbourne, Victoria, 3083, Australia. [email protected].
8 Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia. [email protected].
9 Beijing Institute of Biotechnology, Beijing, 100071, China. [email protected].

PMID: 29343689 DOI: 10.1038/s41598-017-18479-4

Abstract

We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike Other α-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the α3β4 and α7 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_V2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba²⁺ currents in a voltage- and state-dependent manner. Inhibition of CA_V2.2 by Eu1.6 was concentration-dependent (IC₅₀ ~1 nM). Significantly, systemic administration of Eu1.6 at doses of 2.5-5.0 μg/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 α-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.

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