Voltage‐Gated Sodium Channels as Therapeutic Targets

Wingerd, Joshua S.; Vetter, Irina; Lewis, Richard J.

doi:10.1002/9781118185537.ch3

Cited by 10 publications

(8 citation statements)

References 351 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By contrast, Na V 1.4 is expressed in skeletal muscle, Na V 1.5 is crucial for the cardiac action potential and Na V 1.6 is expressed at nodes of Ranvier of myelinated neurons where it is involved in saltatory action potential conduction [27]. Furthermore, loss of function mutations in the Na V 1.7 gene are known to underlie congenital indifference to pain in humans, whereas gain of function mutations produce erythromelalgia and paroxysmal extreme pain disorder, conditions characterized by episodes of uncontrollable pain [28,29].…”

Section: Discussionmentioning

confidence: 96%

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

et al. 2015

Self Cite

View full text Add to dashboard Cite

Some venomous cone snails feed on small fishes using an immobilizing combination of synergistic venom peptides that target K v and Na v channels. As part of this envenomation strategy, d-conotoxins are potent ichtyotoxins that enhance Na v channel function. d-Conotoxins belong to an ancient and widely distributed gene superfamily, but any evolutionary link from ancestral worm-eating cone snails to modern piscivorous species has not been elucidated. Here, we report the discovery of SuVIA, a potent vertebrate-active d-conotoxin characterized from a vermivorous cone snail (Conus suturatus). SuVIA is equipotent at hNa V 1.3, hNa V 1.4 and hNa V 1.6 with EC 50 s in the low nanomolar range. SuVIA also increased peak hNa V 1.7 current by approximately 75% and shifted the voltage-dependence of activation to more hyperpolarized potentials from -15 mV to -25 mV, with little effect on the voltage-dependence of inactivation. Interestingly, the proximal venom gland expression and pain-inducing effect of SuVIA in mammals suggest that d-conotoxins in vermivorous cone snails play a defensive role against higher order vertebrates. We propose that d-conotoxins originally evolved in ancestral vermivorous cones to defend against larger predators including fishes have been repurposed to facilitate a shift to piscivorous behaviour, suggesting an unexpected underlying mechanism for this remarkable evolutionary transition.

show abstract

Section: Discussionmentioning

confidence: 96%

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…TTX is active on Na v 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 subtypes in the nanomolar range (IC 50 < 10 nM). Na v 1.6 is sensitive to 1 nM TTX (Wingerd et al., ). All other channels (Na v 1.5, 1.8 and 1.9) show a low sensitivity to TTX being in the μM range.…”

Section: Assessmentmentioning

confidence: 99%

Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods

Knutsen¹,

Alexander²,

Barregård³

et al. 2017

EFS2

View full text Add to dashboard Cite

Tetrodotoxin (TTX) and its analogues are produced by marine bacteria and have been detected in marine bivalves and gastropods from European waters. The European Commission asked EFSA for a scientific opinion on the risks to public health related to the presence of TTX and TTX analogues in marine bivalves and gastropods. The Panel on Contaminants in the Food Chain reviewed the available literature but did not find support for the minimum lethal dose for humans of 2 mg, mentioned in various reviews. Some human case reports describe serious effects at a dose of 0.2 mg, corresponding to 4 lg/kg body weight (bw). However, the uncertainties on the actual exposure in the studies preclude their use for derivation of an acute reference dose (ARfD). Instead, a group ARfD of 0.25 lg/kg bw, applying to TTX and its analogues, was derived based on a TTX dose of 25 lg/kg bw at which no apathy was observed in an acute oral study with mice, applying a standard uncertainty factor of 100. Estimated relative potencies for analogues are lower than that of TTX but are associated with a high degree of uncertainty. Based on the occurrence data submitted to EFSA and reported consumption days only, average and P95 exposures of 0.00-0.09 and 0.00-0.03 lg/kg bw, respectively, were calculated. Using a large portion size of 400 g bivalves and P95 occurrence levels of TTX, with exception of oysters, the exposure was below the group ARfD in all consumer groups. A concentration below 44 lg TTX equivalents/kg shellfish meat, based on a large portion size of 400 g, was considered not to result in adverse effects in humans. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) methods are the most suitable for identification and quantification of TTX and its analogues, with LOQs between 1 and 25 lg/kg.

show abstract

“…This channel contains one alpha subunit and one to three small beta subunits. There are 9 alpha subunits of the Nav channel (Nav 1 to 9) (Wingerd, Vetter, & Lewis, 2012), and originally they were divided into tetrodotoxin (TTX)-sensitive (Nav 1, 2, 3 and 7) and TTX insensitive. The alpha subunits contain 4 homologous domains, each with 6 hydrophobic transmembrane segments.…”

Section: Saxitoxin Groupmentioning

confidence: 99%

Derivation of toxicity equivalency factors for marine biotoxins associated with Bivalve Molluscs

Botana

Heß

Munday

et al. 2017

Trends in Food Science & Technology

View full text Add to dashboard Cite

Background Seafood toxins pose an important risk to human health, and maximum levels were imposed by regulatory authorities throughout the world. Several toxin groups are known, each one with many analogues of the major toxin. Regulatory limits are set to ensure that commercially available seafood is not contaminated with unsafe levels. Scope and Approach The mouse bioassay was used to measure the toxicity in seafood extracts to determine if a sample exceeded regulatory limits. The advantage of this approach was to provide an estimation of the total toxicity in the sample. As instrumental methods of analysis advance and serve as replacements to the mouse bioassay, the challenge is translating individual toxin concentrations into toxicity to determine whether regulatory limits have been exceeded. Such analyses provide accurate quantitation of the toxin Please note that this is an author-produced PDF of an article accepted for publication following peer review. The definitive publisher-authenticated version is available on the publisher Web site. analogues, by they have widely dissimilar potencies. Thus, knowledge of the relative toxicities is required for risk assessment and determining overall toxicity. The ratios between the toxicity of the analogues and that of a reference compound within the same toxin group are termed "Toxicity Equivalency Factors" (TEFs). Key Findings and Conclusions In this document, the requirements for determining TEFs of toxin analogues are described, and recommendations for research to further refine TEFs are identified. The proposed TEFs herein, when applied to toxin analogue concentrations determined using analytical methods, will provide a base to determine overall toxicity, thereby protecting human health. Highlights ► Marine toxins TEF are revised according to recent toxicology studies. ► TEF for each toxin group are proposed. ► The proposed TEF were agreed by a joint FAO-WHO working group.

show abstract

Voltage‐Gated Sodium Channels as Therapeutic Targets

Cited by 10 publications

References 351 publications

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods

Derivation of toxicity equivalency factors for marine biotoxins associated with Bivalve Molluscs

Contact Info

Product

Resources

About