Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels NaV1.2, 1.6 and 1.7

Fiedler, Brian; Zhang, Min Min; Buczek, Oga; Azam, Layla; Bułaj, Grzegorz; Norton, Raymond S.; Olivera, Baldomero M.; Yoshikami, Doju

doi:10.1016/j.bcp.2008.03.019

Cited by 56 publications

(60 citation statements)

References 46 publications

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“…Recent estimates suggest that each species of cone snail produces hundreds to thousands of conotoxins, the majority of which remain pharmacologically uncharacterized [4,17]. Not surprisingly, many conotoxins affect action potential initiation and propagation, including the m-and mO-conotoxins that block the pore or alter Na V channel gating, [1,[18][19][20], the d-conotoxins that delay Na V inactivation by binding to site 6, and the i-conotoxins that enhance Na V channel opening [21][22][23]. While inhibition or enhanced activation of Na V can cause paralysis, cardiac arrhythmias or epilepsy in the case of central Na V , the precise role of conopeptides targeting Na V channels in prey capture and/or defence is unclear.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Section: Discussionmentioning

confidence: 99%

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

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“…The oxida- Other Toxins-Syntheses of -GIIIA, and -PIIIA[R14Q] were performed essentially as previously described (12,13). The synthesis of (O §-GVIIJ) 2 (a dimer in which Cys-24 of one monomer was disulfide-bonded to its counterpart on the other monomer) was described recently (5).…”

Section: Methodsmentioning

confidence: 99%

“…8C and Table 4), which indicates that the two peptides (-and O §-conotoxins) do not compete for the same site to block the channel. On the other hand, the rate of block by 10 M (O §-GVIIJ) 2 (i.e. the O §-GVIIJ dimer) was slightly but significantly, decreased by the presence of -PIIIA[R14Q] (Fig.…”

Section: -Tyrmentioning

confidence: 99%

“…Four classes of conopeptides have been shown to affect VGSC activity. Peptides belonging to the -and ␦-families promote activation and inhibit inactivation, respectively, whereas the -and O-conotoxins inhibit VGSCs by either blocking the Na ϩ conductance pore or preventing channel activation, respectively (2,3). Recently, the founding member of a fifth class of VGSC inhibitors was identified that blocks the channel through interaction with a previously unidentified neurotoxin binding site, site 8 ( Fig.…”

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confidence: 99%

“…We show here that pre-equilibrating rNa V 1.4 with nearly saturating levels of -PIIIA[R14Q] did not interfere with the block by O §-GVII-J SSG . In contrast, the rate of block by a dimer of O §-GVIIJ, (O §-GVIIJ) 2 , whose monomers were disulfide-bonded to each other via the thiols of their Cys-24 residues (5), was decreased by the presence of -PIIIA[R14Q]. These results lead us to conclude that sites 1 and 8 are distinct although not very far apart.…”

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confidence: 99%

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Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ

Green

Gajewiak

Chhabra

et al. 2016

Journal of Biological Chemistry

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Cone snail toxins are well known blockers of voltage-gated sodium channels, a property that is of broad interest in biology and therapeutically in treating neuropathic pain and neurological disorders. Although most conotoxin channel blockers function by direct binding to a channel and disrupting its normal ion movement, conotoxin O §-GVIIJ channel blocking is unique, using both favorable binding interactions with the channel and a direct tether via an intermolecular disulfide bond. Disulfide exchange is possible because conotoxin O §-GVIIJ contains an S-cysteinylated Cys-24 residue that is capable of exchanging with a free cysteine thiol on the channel surface. Here, we present the solution structure of an analog of O §-GVIIJ (GVIIJ[C24S]) and the results of structure-activity studies with synthetic O §-GVIIJ variants. GVIIJ[C24S] adopts an inhibitor cystine knot structure, with two antiparallel ␤-strands stabilized by three disulfide bridges. The loop region linking the ␤-strands (loop 4) presents residue 24 in a configuration where it could bind to the proposed free cysteine of the channel (Cys-910, rat Na V 1.2 numbering; at site 8). The structure-activity study shows that three residues (Lys-12, Arg-14, and Tyr-16) located in loop 2 and spatially close to residue 24 were also important for functional activity. We propose that the interaction of O §-GVIIJ with the channel depends on not only disulfide tethering via Cys-24 to a free cysteine at site 8 on the channel but also the participation of key residues of O §-GVIIJ on a distinct surface of the peptide.Marine snails of the genus Conus employ a complex venom mixture to subdue prey and as an effective means of defending against predation. The active venoms contain an array of peptides that bind to and modulate the properties of ion channels, G-protein-coupled receptors, and neurotransmitter receptors (1). Several peptides modulate the activities of voltage-gated sodium channels (VGSCs), 4 which are implicated in numerous neurological disorders, as well as neuropathic pain. Four classes of conopeptides have been shown to affect VGSC activity. Peptides belonging to the -and ␦-families promote activation and inhibit inactivation, respectively, whereas the -and O-conotoxins inhibit VGSCs by either blocking the Na ϩ conductance pore or preventing channel activation, respectively (2, 3). Recently, the founding member of a fifth class of VGSC inhibitors was identified that blocks the channel through interaction with a previously unidentified neurotoxin binding site, site 8 (Fig. 1A) (4).O §-GVIIJ is a 35-residue peptide isolated from the venom of the piscivorous snail Conus geographus (Fig. 1B). In vitro folding of linear O §-GVIIJ with thiol-reactive oxidants (i.e. glutathione, L-cystine, or cystamine) resulted in adducts where Cys-24 was disulfide-bonded with glutathione, cysteine, or cysteamine, respectively (abbreviated as GVIIJ SSG , GVIIJ SSC , and GVIIJ SSEA , respectively; see Fig. 1C for structures). Of these, the GVIIJ SSC variant most closely resembled ...

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N‐ and c‐terminal extensions of μ‐conotoxins increase potency and selectivity for neuronal sodium channels

et al. 2012

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μ-Conotoxins are peptide blockers of voltage-gated sodium channels (sodium channels), inhibiting tetrodotoxin-sensitive neuronal (Na(v) 1.2) and skeletal (Na(v) 1.4) subtypes with highest affinity. Structure-activity relationship studies of μ-conotoxins SIIIA, TIIIA, and KIIIA have shown that it is mainly the C-terminal part of the three-loop peptide that is involved in binding to the sodium channel. In this study, we characterize the effect of N- and C-terminal extensions of μ-conotoxins SIIIA, SIIIB, and TIIIA on their potency and selectivity for neuronal versus muscle sodium channels. Interestingly, extending the N- or C-terminal of the peptide by introducing neutral, positive, and/or negatively charged residues, the selectivity of the native peptide can be altered from neuronal to skeletal and the other way around. The results from this study provide further insight into the binding profile of μ-conotoxins at voltage-gated sodium channels, revealing that binding interactions outside the cysteine-stablilized loops can contribute to μ-conotoxin affinity and sodium channel selectivity.

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Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels NaV1.2, 1.6 and 1.7

Cited by 56 publications

References 46 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

Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ

N‐ and c‐terminal extensions of μ‐conotoxins increase potency and selectivity for neuronal sodium channels

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