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

ABSTRACT: We here describe a novel ?-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike other ?-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the ?3?4 and ?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 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 ~1?nM). Significantly, systemic administration of Eu1.6 at doses of 2.5-5.0??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 ?-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.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5772529 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A novel α-conopeptide Eu1.6 inhibits N-type (Ca<sub>V</sub>2.2) calcium channels and exhibits potent analgesic activity.

Liu Zhuguo Z Bartels Peter P Sadeghi Mahsa M Du Tianpeng T Dai Qing Q Zhu Cui C Yu Shuo S Wang Shuo S Dong Mingxin M Sun Ting T Guo Jiabin J Peng Shuangqing S Jiang Ling L Adams David J DJ Dai Qiuyun Q

Scientific reports 20180117 1

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 c ...[more]

PMID: 29343689

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Project description:In the mammalian brain, presynaptic CaV 2 channels play a pivotal role in synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the active zone of presynaptic terminals. However, the distribution and modulation of CaV 2.2 channels at plastic hippocampal synapses remains to be elucidated. Here, we assess CaV 2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. We show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+ transients, mediated by increased levels of CaV 2.2 channels at the presynaptic site. This work focused further on the role of α2 δ-1 subunits, important regulators of synaptic transmission and CaV 2.2 channel abundance at the presynaptic membrane. We found that α2 δ-1 overexpression reduces the contribution of CaV 2.2 channels to total Ca2+ flux without altering the amplitude of the Ca2+ transients. Levels of endogenous α2 δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α2 δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV 2.2 channels and novel roles for α2 δ-1 during synaptic plastic adaptation. KEY POINTS: The roles of CaV 2.2 channels and α2 δ-1 in homeostatic synaptic plasticity in hippocampal neurons in culture were examined. Chronic silencing of neuronal activity resulted in elevated presynaptic Ca2+ transients, mediated by increased levels of CaV 2.2 channels at presynaptic sites. The level of endogenous α2 δ-1 decreased during homeostatic synaptic plasticity, whereas overexpression of α2 δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV 2.2 channels and novel roles for α2 δ-1 during synaptic plastic adaptation.

Dataset Information

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

Publications

A novel α-conopeptide Eu1.6 inhibits N-type (Ca<sub>V</sub>2.2) calcium channels and exhibits potent analgesic activity.

Similar Datasets

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