Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA

Wang, Fei; Yan, Zhenzhen; Liu, Zhuguo; Wang, Sheng; Wu, Qiaoling; Yu, Shuo; Ding, Jiuping; Dai, Qiuyun

doi:10.1016/j.neuropharm.2015.08.047

Cited by 34 publications

(42 citation statements)

References 36 publications

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“…Generally, a precipitating solvent is used to precipitate most proteins in plasma and keep the analytes in solution [ 24 , 28 , 29 ]. In the present assay, a mixed solvent of methanol/acetonitrile (50:50, v / v ) was used.…”

Section: Discussionmentioning

confidence: 99%

“…These peptide conotoxins selectively target ion channels, e.g., Na + , K + and Ca 2+ channels, or membrane receptors (nAChR, NMDAR and G-protein-coupled receptors) [ 12 , 13 , 14 , 15 ]. For example, α-conotoxins GI, GIA and GII are potent antagonists for nicotine acetylcholine receptors (nAChRs) [ 16 , 17 , 18 ]; μ-conotoxins GIIIA, GIIIB and GIIIC selectively target sodium ion channels [ 19 , 20 , 21 ]; ω-conotoxins GVIA, GVIB, GVIC, GVIIA and GVIIB inhibit calcium ion channels [ 22 , 23 , 24 ]. GI ( Figure 1 ) contains 13 amino acid residues and two disulfide bridges and is the most poisonous of all the peptide toxins in the venom of C. geographus .…”

Section: Introductionmentioning

confidence: 99%

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Sensitive Detection of α-Conotoxin GI in Human Plasma Using a Solid-Phase Extraction Column and LC-MS/MS

Yu¹,

Yang²,

Yan³

et al. 2017

Toxins

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α-conotoxin GI, a short peptide toxin in the venom of Conus geographus, is composed of 13 amino acids and two disulfide bonds. It is the most toxic component of Conus geographus venom with estimated lethal doses of 0.029–0.038 mg/kg for humans. There is currently no reported analytical method for this toxin. In the present study, a sensitive detection method was developed to quantify GI in human plasma using a solid-phase extraction (SPE) column (polystyrene–divinyl benzene copolymer) combined with liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the multiple reaction monitoring (MRM) mode. The plasma samples were treated with a protein precipitating solvent (methanol: acetonitrile = 50:50, v/v). GI in the solvent was efficiently extracted with an SPE column and was further separated by a Grace Alltima HP C18 (50 × 2.1 mm, 5 μm) column at a flow rate of 0.4 mL/min. Water (with 2% methanol) acetonitrile (with 0.1% acetic acid) was selected as the mobile phase combination used in a linear gradient system. α-Conotoxin GI was analyzed by an API 4000 triple quadrupole mass spectrometer. In the method validation, the linear calibration curve in the range of 2.0 to 300.0 ng/mL had correlation coefficients (r) above 0.996. The recovery was 57.6–66.8% for GI and the internal standard. The lower limit of quantification (LLOQ) was 2 ng/mL. The intra- and inter-batch precisions were below 6.31% and 8.61%, respectively, and the accuracies were all within acceptance. GI was stable in a bench-top autosampler through long-term storage and freeze/thaw cycles. Therefore, this method is specific, sensitive and reliable for quantitative analysis of α-conotoxin GI in human plasma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sensitive Detection of α-Conotoxin GI in Human Plasma Using a Solid-Phase Extraction Column and LC-MS/MS

Yu¹,

Yang²,

Yan³

et al. 2017

Toxins

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“…In December 2004, the Food and Drug Administration (FDA) approved Prialt ® (commercial name for MVIIA) for the treatment of severe chronic pain using an intrathecal pump system to deliver the drug into the cerebrospinal fluid. Consistent with this action, injection of MVIIA into mammals caused important neuromuscular effects such as decrease of spontaneous and coordinated locomotor activity and tremors [ 45 ]. It was shown that these effects and the pain relief caused by delivery of MVIIA into the cerebrospinal fluid are mediated by inhibition of the release of pro-nociceptive neurochemicals such as glutamate, calcitonin gene-related peptide (CGRP), and substance P into the brain and spinal cord [ 46 , 47 ].…”

Section: Classification Of ω-Conotoxins That Target Ca Vmentioning

confidence: 99%

Conotoxins as Tools to Understand the Physiological Function of Voltage-Gated Calcium (CaV) Channels

et al. 2017

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Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human tissues and organs. CaV channels are divided into two groups depending on the membrane potential required to activate them: High-voltage activated (HVA, CaV1.1–1.4; CaV2.1–2.3) and Low-voltage activated (LVA, CaV3.1–3.3). HVA channels are highly expressed in brain (neurons), heart, and adrenal medulla (chromaffin cells), among others, and are also classified into subtypes which can be distinguished using pharmacological approaches. Cone snails are marine gastropods that capture their prey by injecting venom, “conopeptides”, which cause paralysis in a few seconds. A subset of conopeptides called conotoxins are relatively small polypeptides, rich in disulfide bonds, that target ion channels, transporters and receptors localized at the neuromuscular system of the animal target. In this review, we describe the structure and properties of conotoxins that selectively block HVA calcium channels. We compare their potency on several HVA channel subtypes, emphasizing neuronal calcium channels. Lastly, we analyze recent advances in the therapeutic use of conotoxins for medical treatments.

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“…However, although Prialt is approved for treating intractable cancer pain in humans it has a narrow therapeutic window and the potential for causing severe CNS side effects (Antanassoff et al, 2000;Penn and Paice, 2000;Miljanich, 2004;Staats et al, 2004;Thompson et al, 2006;Wallace et al, 2006;Ver et al, 2008). The toxicity of MVIIA has recently been attributed to a methionine residue at position 12 of the toxin molecule, which is known to dock to a hydrophobic binding pocket comprised of residues I300, F302, L305 of the Cav2.2 subunit (Wang et al, 2016).…”

Section: U-conotoxinsmentioning

confidence: 99%

Block of voltage-gated calcium channels by peptide toxins

Bourinet

Zamponi

2017

Neuropharmacology

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Venoms from various predatory species, such as fish hunting molluscs scorpions, snakes and arachnids contain a large spectrum of toxins that include blockers of voltage-gated calcium channels. These peptide blockers act by two principal manners - physical occlusion of the pore and prevention of activation gating. Many of the calcium channel-blocking peptides have evolved to tightly occupy their binding pocket on the principal pore forming subunit of the channel, often rendering block poorly reversible. Moreover, several of the best characterized blocking peptides have developed a high degree of channel subtype selectivity. Here we give an overview of different types of calcium channel-blocking toxins, their mechanism of action, channel subtype specificity, and potential use as therapeutic agents. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'

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Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA

Cited by 34 publications

References 36 publications

Sensitive Detection of α-Conotoxin GI in Human Plasma Using a Solid-Phase Extraction Column and LC-MS/MS

Sensitive Detection of α-Conotoxin GI in Human Plasma Using a Solid-Phase Extraction Column and LC-MS/MS

Conotoxins as Tools to Understand the Physiological Function of Voltage-Gated Calcium (CaV) Channels

Block of voltage-gated calcium channels by peptide toxins

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