Conotoxins of the O-superfamily affecting voltage-gated sodium channels

Heinemann, Stefan H.; Leipold, Enrico

doi:10.1007/s00018-007-6565-5

Cited by 50 publications

(55 citation statements)

References 48 publications

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“…S7), but the peptide may stabilize the channel in some other inactivated state, such as a slow-inactivated state that may involve conformational coupling between the pore and voltage-sensor domains (31). Alternatively, the GVIIJ peptides may inhibit channel activation by interfering with the channels' voltage sensors, similar to what gating modifiers such as μO-MrVIB, Protox II, and HwTx-IV do (22,23,(32)(33)(34), but possibly allosterically. It might be noted that, at saturating toxin concentrations, the level (or efficacy) of block of Na V 1.7 by Protox II and of Na V 1.4 by HwTx-IV are 95% (32) and 41% (34), respectively, and they may represent precedents for the partial efficacy of block manifested by the GVIIJ peptides.…”

Section: Discussionmentioning

confidence: 99%

A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ

Gajewiak¹,

Azam²,

Imperial³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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A cone snail venom peptide, μO §-conotoxin GVIIJ from Conus geographus, has a unique posttranslational modification, S-cysteinylated cysteine, which makes possible formation of a covalent tether of peptide to its target Na channels at a distinct ligandbinding site. μO §-conotoxin GVIIJ is a 35-aa peptide, with 7 cysteine residues; six of the cysteines form 3 disulfide cross-links, and one (Cys24) is S-cysteinylated. Due to limited availability of native GVIIJ, we primarily used a synthetic analog whose Cys24 was S-glutathionylated (abbreviated GVIIJ SSG ). The peptide-channel complex is stabilized by a disulfide tether between Cys24 of the peptide and Cys910 of rat (r) Na V 1.2. A mutant channel of rNa V 1.2 lacking a cysteine near the pore loop of domain II (C910L), was >10 3 -fold less sensitive to GVIIJ SSG than was wild-type rNa V 1.2. In contrast, although rNa V 1.5 was >10 4 -fold less sensitive to GVIIJ SSG than Na V 1.2, an rNa V 1.5 mutant with a cysteine in the homologous location, rNa V 1.5[L869C], was >10 3 -fold more sensitive than wildtype rNa V 1.5. The susceptibility of rNa V 1.2 to GVIIJ SSG was significantly altered by treating the channels with thiol-oxidizing or disulfide-reducing agents. Furthermore, coexpression of rNa V β2 or rNa V β4, but not that of rNa V β1 or rNa V β3, protected rNa V 1.1 to -1.7 (excluding Na V 1.5) against block by GVIIJ SSG . Thus, GVIIJrelated peptides may serve as probes for both the redox state of extracellular cysteines and for assessing which Na V β-and Na V α-subunits are present in native neurons.oltage-gated sodium channels (VGSCs) are responsible for the upstroke of action potentials in excitable tissues. Each VGSC is composed of a pore-and voltage sensor-bearing α-subunit and one or more auxiliary β-subunits. Mammals have nine α-subunit isoforms (Na V 1.1 to -1.9) and four β-subunit isoforms (Na V β1 to -β4) (1). An Na V 1 has about 2,000-aa residues arranged in four homologous domains, where each domain has six transmembrane spanning segments with an extracellular "pore" loop between segments 5 and 6 (1, 2); furthermore, each Na V 1 has about a dozen extracellular cysteine residues, all located in or near the pore loops. For the most part, not much is known about these cysteines (including whether they are disulfide bonded).Na V β-subunits can affect the function and cellular localization of Na V 1s (1, 3-5). Each Na V β-subunit has some 200-aa residues and consists of a single transmembrane segment with a large extracellular domain and a smaller intracellular domain (1). Na V β2-and Na V β4-subunits, unlike Na V β1-and Na V β3-subunits, are disulfide bonded to α-subunits (1, 6). A given neuron can have multiple isoforms of these subunits whose identities are challenging to appraise pharmacologically (7).Toxins that target VGSCs have been invaluable for probing the structure and function of these channels. Venoms are a rich source of such toxins. For example, in Conus snails, four families of neuroactive peptides have been characterized that target VGSCs:...

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Section: Discussionmentioning

confidence: 99%

A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ

Gajewiak¹,

Azam²,

Imperial³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Many of the more recently discovered ligands that target VGSCs are components of animal venoms (Al-Sabi et al, 2006;Billen et al, 2008). The peptide toxins from cone snail venoms are a particularly rich source (Terlau and Olivera, 2004), and at least four families of conopeptides target VGSCs, each via a different mechanism: -conotoxins, like the action of TTX and STX, block the channel's pore (Catterall et al, 2007); O-conotoxins are gating modifiers that block channel activation (Zorn et al, 2006;Heinemann and Leipold, 2007;Leipold et al, 2007); -conotoxins promote channel activation (Fiedler et al, 2008); and ␦-conotoxins inhibit fast inactivation (Leipold et al, 2005;West et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Na_Vβ Subunits Modulate the Inhibition of Na_V1.8 by the Analgesic Gating Modifier μO-Conotoxin MrVIB

Wilson¹,

Zhang²,

Azam³

et al. 2011

J Pharmacol Exp Ther

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Voltage-gated sodium channels (VGSCs) consist of a pore-forming ␣-subunit and regulatory ␤-subunits. Several families of neuroactive peptides of Conus snails target VGSCs, including Oconotoxins and -conotoxins. Unlike -conotoxins and the guanidinium alkaloid saxitoxin (STX), which are pore blockers, O-conotoxins MrVIA and MrVIB inhibit VGSCs by modifying channel gating. O-MrVIA/B can block Na V 1.8 (a tetrodotoxinresistant isoform of VGSCs) and have analgesic properties. The effect of Na V ␤-subunit coexpression on susceptibility to block by O-MrVIA/B and STX has, until now, not been reported. Here, we show that ␤1-, ␤2-, ␤3-, and ␤4-subunits, when individually coexpressed with Na V 1.8 in Xenopus laevis oocytes, increased the k on of the block produced by O-MrVIB (by 3-, 32-, 2-, and 7-fold, respectively) and modestly decreased the apparent k off . Strong depolarizing prepulses markedly accelerated MrVIB washout with rates dependent on ␤-subunit coexpression. Thus, coexpression of ␤-subunits with Na V 1.8 can strongly influence the affinity of the conopeptide for the channel. This observation is of particular interest because ␤-subunit expression can be dynamic, e.g., ␤2-expression is up-regulated after nerve injury (J Neurosci, 25: 10970 -10980, 2005); therefore, the effectiveness of a O-conotoxin as a channel blocker could be enhanced by the conditions that may call for its use therapeutically. In contrast to MrVIB's action, the STX-induced block of Na V 1.8 was only marginally, if at all, affected by coexpression of any of the ␤-subunits. Our results raise the possibility that O-conotoxins and perhaps other gating modifiers may provide a means to functionally assess the ␤-subunit composition of VGSC complexes in neurons.

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“…O-superfamily toxins exhibit a characteristic pattern of 6 cysteines (C-C-CC-C-C) that form three disulfide bonds. Members of this family are known modulators of voltage-sensitive calcium, potassium, and sodium channels (44,46). Alignment of the novel O-conotoxins with other members of the O-superfamily revealed high sequence similarity to the O2 gene superfamily (Fig.…”

Section: Identification Of Novel Conotoxin Transcripts In C Victoriaementioning

confidence: 99%

Embryonic Toxin Expression in the Cone Snail Conus victoriae

Safavi-Hemami

Siero

Kuang³

et al. 2011

Journal of Biological Chemistry

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Predatory marine cone snails (genus Conus) utilize complex venoms mainly composed of small peptide toxins that target voltage-and ligand-gated ion channels in their prey. Although the venoms of a number of cone snail species have been intensively profiled and functionally characterized, nothing is known about the initiation of venom expression at an early developmental stage. Here, we report on the expression of venom mRNA in embryos of Conus victoriae and the identification of novel ␣-and O-conotoxin sequences. Embryonic toxin mRNA expression is initiated well before differentiation of the venom gland, the organ of venom biosynthesis. Structural and functional studies revealed that the embryonic ␣-conotoxins exhibit the same basic three-dimensional structure as the most abundant adult toxin but significantly differ in their neurological targets. Based on these findings, we postulate that the venom repertoire of cone snails undergoes ontogenetic changes most likely reflecting differences in the biotic interactions of these animals with their prey, predators, or competitors. To our knowledge, this is the first study to show toxin mRNA transcripts in embryos, a finding that extends our understanding of the early onset of venom expression in animals and may suggest alternative functions of peptide toxins during development.

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Conotoxins of the O-superfamily affecting voltage-gated sodium channels

Cited by 50 publications

References 48 publications

A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ

A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ

Na_Vβ Subunits Modulate the Inhibition of Na_V1.8 by the Analgesic Gating Modifier μO-Conotoxin MrVIB

Embryonic Toxin Expression in the Cone Snail Conus victoriae

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Conotoxins of the O-superfamily affecting voltage-gated sodium channels

Cited by 50 publications

References 48 publications

A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ

A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ

NaVβ Subunits Modulate the Inhibition of NaV1.8 by the Analgesic Gating Modifier μO-Conotoxin MrVIB

Embryonic Toxin Expression in the Cone Snail Conus victoriae

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Na_Vβ Subunits Modulate the Inhibition of Na_V1.8 by the Analgesic Gating Modifier μO-Conotoxin MrVIB