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

Liu, Z, Bartels, P, Sadeghi, M, Du, T, Dai, Q, Zhu, C, Yu, S, Wang, S, Dong, M, Sun, T, Guo, J, Peng, S, Jiang, L, Adams, D and Dai, Q 2018, 'A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity', Scientific Reports, vol. 8, no. 1, pp. 1-13.


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Title A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity
Author(s) Liu, Z
Bartels, P
Sadeghi, M
Du, T
Dai, Q
Zhu, C
Yu, S
Wang, S
Dong, M
Sun, T
Guo, J
Peng, S
Jiang, L
Adams, D
Dai, Q
Year 2018
Journal name Scientific Reports
Volume number 8
Issue number 1
Start page 1
End page 13
Total pages 13
Publisher Nature
Abstract We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong antinociceptive 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 GABAB receptor activation. In HEK293 cells expressing CaV2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba2+ currents in a voltage- and state-dependent manner. Inhibition of CaV2.2 by Eu1.6 was concentration-dependent (IC50 ~1nM). Signifcantly, systemic administration of Eu1.6 at doses of 2.5–5.0μg/kg exhibited potent analgesic activities in rat partial sciatic nerve injury and chronic constriction injury pain models. Furthermore, Eu1.6 had no signifcant side-efect on spontaneous locomotor activity, cardiac and respiratory function, and drug dependence in mice. These fndings 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.
Subject Chemical Sciences not elsewhere classified
Medical and Health Sciences not elsewhere classified
Keyword(s) Nicotinic acetylcholine-receptors
nAChR alpha-3-beta-2
Omega-conotoxins
Conus-marmoreus
Pain
Diversity
Rat
alpha-9-alpha-10
Activation
Ziconotide
DOI - identifier 10.1038/s41598-017-18479-4
Copyright notice © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License
ISSN 2045-2322
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