Voltage-dependent sodium channels are integral plasma membrane proteins responsible for the rapidly rising phase of action potentials in most excitable tissues and as such are specifically targeted by many neurotoxins. These toxins occupy at least six identified (receptor sites 1-5 (Catterall, 1986), and receptor site 6 (Fainzilber et al., 1994)) and two unidentified (CsTx ()and GPT (Catterall, 1992)) receptor sites on the rat brain sodium channel and have been used as tools for functional mapping and characterization of the channel (Catterall, 1986, 1992; Fainzilber et al., 1994).

Over the past decade a number of selective toxin ligands have been characterized that compete directly on their binding but by various criteria cannot share precisely the same receptor binding sites (Adams and Olivera, 1994; Gordon et al., 1992). Receptor sites are thought to overlap when they appear to be targeted by a number of different toxins that induce similar pharmacological effects and compete in binding assays. Complexes of such overlapping sites have been termed macrosites (Olivera et al., 1991). We suggest that a receptor site be defined as the combined points of attachment/recognition sites that are directly involved in the binding interactions with a toxin. A macrosite, in this context, may include distinct receptor sites for several toxins, each with its own unique points of attachment. Some of these recognition sites may be shared by different toxins that bind in the same macrosite. For example, receptor site 1 on the sodium channel (Catterall, 1986, 1992) binds the blockers tetrodotoxin, saxitoxin, and µ-conotoxins. We suggest that this is in fact a macrosite, since tetrodotoxin and saxitoxin do not share all of their attachment points (Terlau et al., 1991). Furthermore, µ-conotoxins selectively bind to skeletal muscle sodium channels (Moczydlowski et al., 1986) on which at least part of their attachment points are distinct from those of saxitoxin (Stephan et al., 1994).

Receptor sites for peptide neurotoxins that inhibit sodium current inactivation are of particular interest for the study of the dynamics of channel gating since neurotoxin binding at these extracellular regions can affect the inactivation process at intramembranal segments of the channel (Catterall, 1992). These are the macrosite that binds sea anemone and -scorpion toxins (site 3 of Catterall(1986)) and the receptor sites for GPT, CsTx, and TxVIA (Gonoi et al., 1986, 1987; Fainzilber et al., 1994). The latter three receptor sites have been shown to be distinct from each other on the basis of binding and pharmacological studies (Catterall and Beress, 1978; Ray et al., 1979; Gonoi et al., 1986, 1987; Fainzilber et al., 1994). Furthermore, TxVIA has the unique property of distinguishing between phyletic variants of sodium channels on the basis of activity but not binding (Fainzilber et al., 1994). Thus subtle differences in the TxVIA receptor site on different channels may be the cause of significant differences in toxin effects; and conversely sequence variabilities in a family of toxins interacting with a single channel subtype may cause differing agonist/antagonist activities. Therefore, the aim of this study was to find a peptide homologous to TxVIA, which would act as an agonist at its receptor site on the rat brain sodium channel. Screening of piscivorous Conus venoms revealed a new conotoxin that competes with TxVIA on binding to both rat brain and molluscan sodium channels and acts as a full agonist in rat brain. This new toxin, designated NgVIA, will serve as a complementary pharmacological probe for the study of the role(s) and structureof the TxVIA receptor site and related receptor sites in modulation of sodium channel gating.

EXPERIMENTAL PROCEDURES

Materials

Column Chromatography

Figure 1: Purification of NgVIA. A, 50 mg of lyophilized venom was extracted as described under ``Experimental Procedures,'' and separated on a Sephadex G-50 column (63 1.42 cm), equilibrated, and eluted in 0.1 M ammonium acetate, pH 7.5, at a flow rate of 5 ml/h and a temperature of 4 °C. B, the marked fraction was further fractionated by reverse phase HPLC on a Vydac C18 column (25 0.46 cm, 5 µm particle size), eluted at a flow rate of 0.5 ml/min with a gradient of acetonitrile in 0.1% trifluoroacetic acid as shown by the dashed line. C, the active fraction (indicated by the arrow in B) was further purified on a Vydac phenyl column (25 0.46 cm, 5 µm particle size) using the same flow rate and solvents. The inset shows complete identity in the superimposed UV spectra sampled by a diode array detector at different time points along the NgVIA peak. D, synthetic NgVIA was prepared as described under ``Experimental Procedures,'' and purified to homogeneity on an Alltech C8 column (25 0.46 cm, 5 µm particle size) at a flow rate of 0.5 ml/min, using a linear gradient of 0-60% acetonitrile, 2-propanol (1:1) in 0.1% trifluoroacetic acid. The lower trace (1) is pure synthetic NgVIA, and the upper trace (2) is an equimolar mix of native and synthetic NgVIA.

Amino Acid Analysis

Peptide Sequencing

Peptide Synthesis

Neuronal Membrane Preparations

Radioiodination

Binding Assays

After incubation for the designated time periods, the reaction mixture was diluted with 2 ml of ice-cold wash buffer and filtered through GF/F (Whatman, U. K.) under vacuum. Filters were rapidly washed an additional two times with 2 ml of buffer. Nonspecific toxin binding was determined in the presence of 1 µM unlabeled TxVIA and typically consisted of 30-35% of total binding, one-third of which was to the filters alone. Binding data were analyzed using the iterative computer program LIGAND (Elsevier Biosoft, U. K.).

Na Flux Assays

Electrophysiology

In Vivo Animal Bioassays

RESULTS

Our primary aim was to identify a small peptide ligand that might act as an agonist at the -conotoxin receptor site in rat brain. Preliminary assays on piscivorous Conus venoms revealed that the venom of C. nigropunctatus contained a <4-kDa fraction that displaced TxVIA from its binding sites on both rat brain synaptosomes and molluscan central nervous system. Therefore this venom was chosen for further fractionation. Fractions were assayed in parallel for toxicity to fish and inhibition of TxVIA binding in both rat and mollusc neuronal membrane preparations.

Purification, Characterization, and Toxicity of Conotoxin NgVIA

The amino acid sequence of the toxin was determined by gas-phase automated Edman sequencing after reduction and pyridylethylation. A single unambiguous sequence of 31 amino acid residues was obtained in two separate runs (Table 1) and was in good correlation with the amino acid composition analysis of the toxin (Table 2). Interestingly, the amino acid sequence of the new toxin included a cysteine framework identical to that of TxVIA, with identical numbers of residues in the intercysteine loops (Fig. 2). Two other residues are identical, and there are a number of similarities in the positioning of hydrophobic residues, although the overall net charges of the peptides are contrasting (Fig. 2).

Figure 2: Sequence comparison of conotoxins that inhibit sodium channel inactivation. Identical residues in all four toxins are shown in bold type and are boxed. The standard one-letter code for amino acid residues (except O = trans-4-hydroxyproline) is used. Spacers () are inserted to show maximal homology. , net hydrophobicity calculated according to Fauchere et al.(1988). References for sequences: NgVIA, this paper; GmVIA, Shon et al.(1994); TxVIA/B, Fainzilber et al.(1991).

As we were unable to verify the amino acid sequence data by mass spectrometry, the peptide was synthesized with free C-terminal and folded as described under ``Experimental Procedures.'' As expected from such a hydrophobic sequence the final yield of active (i.e. correctly folded) peptide was low, averaging 3 nmol of active toxin/10 mg of crude synthetic peptide (folding efficiencies ranged from 0.1 to 0.5%). The final purified product co-eluted with native NgVIA in reverse phase HPLC (Fig. 1D) and had the same activity as native toxin in electrophysiological tests and in vivo assays in rat brain (see below).

The paralytic activity of NgVIA was examined in bioassays on fish (Gambusia), snails (Patella), and fly larvae (Sarcophaga). Although the toxin has potent paralytic activity on fish (ED = 2.8 pmol/100 mg of body weight) and snails (ED = 14.5 pmol/100 mg), there were no observable effects on fly larvae at doses of up to 250 pmol/100 mg.

Conotoxin NgVIA Effects on Sodium Current in Molluscan Neurons

Figure 3: Inhibition of voltage-dependent sodium current inactivation by TxVIA and NgVIA. Sodium currents at 10 mV were recorded from caudodorsal neurons of the snail L. stagnalis in the whole cell voltage clamp mode. The effects of 1.2 µM TxVIA (A), 1 µM venom-derived NgVIA (B), and 0.8 µM synthetic NgVIA (C) are shown. Left panels are control currents, middle panels show currents recorded in the presence of the toxin, and right panels show currents recorded after 1 min of wash out of the toxin. The data shown are representative results from a number of different cells. Capacitive transients were clipped in the illustrations. Calibration bars are 50 ms and 0.5 nA.

Effects of Conotoxin NgVIA on TxVIA Binding and on Sodium Flux

Figure 4: Pharmacology of NgVIA in rat brain and snail central nervous system membrane preparations. A, inhibition of I-TxVIA binding by NgVIA. Neuronal membranes were incubated with 0.2 nMI-TxVIA and increasing concentrations of NgVIA. The amount of I-TxVIA bound at each data point is expressed as a percentage of the maximal specific binding in the system. Circles,Helix central nervous system (IC = 59.4 ± 11.4 nM), full triangles, rat brain synaptosomes (IC = 4.9 ± 1.2 nM, empty triangles, lysed rat brain synaptosomes (IC = 18.7 ± 4.4 nM). B, NgVIA and TxVIA effects on Na influx in rat brain synaptosomes. Synaptosomes were incubated with toxins as described under ``Experimental Procedures,'' and net influx of Na after 30 s was determined. Enhancement of veratridine (Ver)-induced flux examined at 2 µM veratridine and 1 µM TxVIA or NgVIA. Results are shown as a percentage of the control flux induced by 2 µM veratridine (1.2 0.3 nmol of sodium/min/mg of protein). The maximal flux obtainable is shown by the rightmost bar (effect of 200 µM veratridine).

The effects of NgVIA on rat brain sodium channels in vitro were examined by Na influx assays in rat brain synaptosomes. NgVIA alone was not able to initiate sodium influx (Fig. 4B), in common with other inactivation-inhibiting toxins (Catterall and Beress, 1978; Fainzilber et al., 1994). However, NgVIA synergically increased the veratridine-stimulated uptake of Na to approximately 3-fold above control levels (Fig. 4B). This is similar to the effect previously obtained with CsTx in this system (Fainzilber et al., 1994).

Effects of Conotoxin NgVIA in Rat Brain

Figure 5: Effects of NgVIA in rat brain in vivo. A, rats were injected intracranially with NgVIA, and their reactions were followed for up to 20 min postinjection. Circles, 100 pmol of NgVIA (n = 2); triangles, 40 pmol of NgVIA (n = 3); squares, 20 pmol of NgVIA (n = 3). B, upon simultaneous injection of 40 pmol of NgVIA with 20 nmol of TxVIA (full triangles, n = 3), the full repertoire of toxic symptoms was seen without very marked change relative to the control of 40 pmol of NgVIA alone (empty triangles). However, when 20 nmol of TxVIA were injected 20 min before administration of 40 pmol of NgVIA (full diamonds, n = 4), the toxic effects were clearly delayed and reduced.

Application of lethal doses of synthetic NgVIA to rats revealed a similar progression of symptoms to that seen with the venom-derived toxin. The rats underwent rapid paralysis and commenced seizures, with death occurring within 10 min. A sublethal dose caused transient hyperactivity and pronounced shaking movements, as seen previously with native NgVIA.

DISCUSSION

In the present study we have identified and characterized a novel peptide conotoxin that affects sodium channel inactivation. As will be detailed below this toxin provides an important complement of the pharmacological tools required for understanding the functional role of different receptor sites in gating mechanisms of sodium channels.

Binding and Pharmacology of Conotoxin NgVIA

There are also qualitative differences in the effects of the two toxins on the sodium current, for example the increase of peak sodium current by NgVIA (Fig. 3). The partial antagonistic effects of TxVIA versus NgVIA might be explained by postulating a higher efficacy of NgVIA activity and/or differences in their binding kinetics. Another possibility is that NgVIA identifies an additional minor population of sodium channels in rat brain, which is not recognized by TxVIA. The lower capacity of TxVIA receptors in rat brain synaptosomes (Fainzilber et al., 1994) as compared with saxitoxin receptors (Ray et al., 1978) is consistent with this possibility. These aspects should be examined in the future when labeled analogs of NgVIA become available.

Binding of NgVIA appears to be at least partially voltage-dependent (Fig. 4A) as is that of CsTx (Gonoi et al., 1987) and the other toxins that inhibit sodium current inactivation. Depolarization of the membrane by lysis of synaptosomes causes a 4-fold increase in the IC for inhibition of I-TxVIA binding by NgVIA. This is comparable with the 5-fold increase in K for sea anemone toxin II action in depolarized neuroblastoma cells (Catterall and Beress, 1978).

The similarity in binding characteristics and interactions of NgVIA with TxVIA in vitro and in vivo to those reported for CsTx (Fainzilber et al., 1994), both qualitatively and quantitatively, suggests that they may bind to closely related sites (see below and Fig. 6). Thus the IC values of both toxins on both rat and mollusc neuronal preparations are similar, as is their synergic effect with veratridine on sodium flux. It is tempting to suggest that NgVIA may have some attachment points in common with those of CsTx; however, the differences between them as regards antagonism in vivo by TxVIA ( Fig. 5and Fainzilber et al.(1994)) suggest that their receptor sites are probably not identical. These differences might also be attributable to different kinetics of binding or efficacy in action of these two toxins. It will be of interest to study these possibilities in the future by direct binding experiments with NgVIA.

Figure 6: A model visualizing locations of peptide neurotoxins affecting sodium current inactivation, bound to their putative receptor sites. The sodium channel extracellular surface is shown from above, with the four homologous repeat domains represented by shaded outlines (I-IV). A, summary of the binding inhibition among the different peptide neurotoxins. The arrows are approximately proportional to the inhibition caused by each toxin on the binding of radiolabeled -scorpion toxin (ScTx) or TxVIA in rat brain synaptosomes. B, illustration of the peptide toxins bound at their putative receptor sites. The receptor site for the sodium channel blocker tetrodotoxin (TTX) has been localized to the extracellular vestibule of the ion-conducting pore (Terlau et al., 1991) and is indicated in the center of the model to facilitate orientation. See text for explanations. ATXII, sea anemone toxin II.

Structures of Conotoxins Affecting Sodium Channel Inactivation

NgVIA is unique in the group of toxins shown in Fig. 2in that it is the only one so far found with significant activity in vertebrates. Indeed it is more potent than CsTx in rat brain by 1 order of magnitude (compare Fig. 5with Fainzilber et al.(1994)). The potent paralytic activity of NgVIA on rats and molluscs and its effects on sodium currents in rat brain synaptosomes and Lymnaea neurons indicate that NgVIA is an agonist of both mammalian and molluscan sodium channels. However, NgVIA cannot be considered a wide range cross-phyletic agonist since it has no discernible paralytic activity on insects. It seems that changes in the composition of the intercysteine loops on a conserved -conotoxin framework may cause significant differences in activity on one variant of sodium channels (i.e. in rat brain), while relatively little change is observed for another variant (i.e. in mollusc central nervous system). NgVIA should be a valuable reference for structure-function analyses of this group of toxins, since it enables a rational analysis of the structural elements necessary for agonist activity of these toxins on the rat brain sodium channel. However, the primary structure variability in this group (Fig. 2) suggests that three-dimensional structural data will be necessary to tackle this question.

A Model for Localization of Receptor Sites of Peptide Neurotoxins That Inhibit Sodium Current Inactivation

For clarity of presentation, we have placed the toxins that do not bind to macrosite 3 (CsTx, GPT, TxVIA) in different domains of the channel. GPT competes with both -scorpion toxin (Gonoi et al., 1986) and TxVIA (Fainzilber et al., 1994) but at concentrations 25-fold higher than its K on mammalian neurons, suggesting that it binds to a distinct site. Therefore GPT is positioned in proximity to both to allow steric interference that may cause the competition between them. CsTx, in contrast, competes at very low concentrations with TxVIA and is completely antagonized by TxVIA in rat brain (Fainzilber et al., 1994). Therefore the receptor sites of CsTx and TxVIA are proposed to partially overlap (Fig. 6B) but are not identical since these two toxins reveal opposite allosteric interactions with alkaloid toxins bound at site 2, such as batrachotoxin and veratridine (Gonoi et al., 1987; Fainzilber et al., 1994).

The partial protection observed by administration of TxVIA prior to NgVIA in rat brain in vivo (Fig. 5) is in contrast to the complete protection or antagonism observed by simultaneous injection of CsTx and TxVIA (Fainzilber et al., 1994). This suggests that the NgVIA and TxVIA receptor sites are partially overlapping, similar to CsTx and TxVIA, but may share different points of attachment (Fig. 6B). It should be noted, however, that steric interference (with no overlap) cannot be excluded (Gordon et al., 1992; Moskowitz et al., 1994). The interaction of NgVIA with the TxVIA receptor site is very similar to that of CsTx (see above). Moreover, the toxic effects of NgVIA are at least partially antagonized by the presence of TxVIA (Fig. 5). On this basis we suggest that the receptor site of NgVIA is partially overlapping with both the CsTx and TxVIA receptor sites (Fig. 6B). The similarity in the binding properties (dependence on membrane polarization, competition with TxVIA, and interaction with veratridine) and activity in vivo between NgVIA and CsTx suggest substantial overlap in their receptor sites.

The model presented in Fig. 6gives a graphic visualization of the different peptide toxins bound to their putative receptor sites on the outer surface of sodium channels while emphasizing the lack of structural information on the molecular level on these receptor sites. All -conotoxins inhibit sodium channel inactivation and as exemplified by NgVIA and TxVIA may do so via binding at distinct receptor sites. Localization of the attachment points comprising these receptor sites may shed light on the mechanism of action of toxins that modify sodium channel gating. The use of TxVIA and NgVIA as pharmacological sensors for minor differences in sodium channel variants provides a rational approach to this complex problem and may contribute to the elucidation of structure-function relationships in sodium channels.

FOOTNOTES

*

This work was supported by a research grant from the Smith Family Laboratory for Psychobiology (to O. K. and M. F.) and by Grant 93-00294 from the U.S.A.-Israel Binational Science Foundation (to E. Z. and D. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed: Molecular Neurobiology, Vrije University, De Boelelaan 1087, 1081 HV Amersterdam, The Netherlands. Fax: 31-20-4447123; mike{at}bio.vu.nl.

()

The abbreviations used are: CsTx, Conus striatus toxin; NgVIA, conotoxin NgVIA from C. nigropunctatus; TxVIA, -conotoxin TxVIA from C. textile; GPT, Goniopora coral toxin; HPLC, high performance liquid chromatography; Fmoc, N-(9-fluorenyl)methoxycarbonyl.

ACKNOWLEDGEMENTS

REFERENCES

1. Adams, M. E., and Olivera, B. M. (1994) Trends Neurosci. 17, 151-155 [CrossRef][Medline] [Order article via Infotrieve]
2. Betner, I., and Foldi, P. (1986) Chromatographia 22, 381-387 [CrossRef]
3. Brussaard, A. B., Lodder, J. C., ter Maat, A., de Vlieger, T. A., and Kits, K. S. (1991) J. Physiol. (Camb.) 441, 385-404 [Abstract/Free Full Text]
4. Catterall, W. A. (1986) Annu. Rev. Biochem. 55, 953-985 [CrossRef][Medline] [Order article via Infotrieve]
5. Catterall, W. A. (1992) Pharmacol. Rev. 72, Suppl. 4, S15-S48
6. Catterall, W. A., and Beress, L. (1978) J. Biol. Chem. 2537393 [Abstract/Free Full Text] -7396
7. Dreijer, A. M. C., and Kits, K. S. (1995) Neuroscience, in press _
8. Fainzilber, M., and Zlotkin, E. (1992) Toxicon 30, 465-469 [Medline] [Order article via Infotrieve]
9. Fainzilber, M., Gordon, D., Hasson, A., Spira, M. E., and Zlotkin, E. (1991) Eur. J. Biochem. 202, 589-595 [Medline] [Order article via Infotrieve]
10. Fainzilber, M., Kofman, O., Zlotkin, E., and Gordon, D. (1994) J. Biol. Chem. 269, 2574-2580 [Abstract/Free Full Text]
11. Fauchere, J. L., Charton, M., Kier, L. B., Verloop, A., and Pliska, V. (1988) Int. J. Pept. Protein Res. 32, 269-278 [Medline] [Order article via Infotrieve]
12. Gonoi, T., Ashida, K., Feller, D., Schmidt, J., Fujiwara, M., and Catterall, W. A. (1986) Mol. Pharmacol. 29, 347-354 [Abstract]
13. Gonoi, T., Ohizumi, Y., Kobayashi, J., Nakamura, H., and Catterall, W. A. (1987) Mol. Pharmacol. 32, 691-698 [Abstract]
14. Gordon, D., Moskowitz, H., Eitan, M., Warner, C., Catterall, W. A., and Zlotkin, E. (1992) Biochemistry 31, 7622-7628 [CrossRef][Medline] [Order article via Infotrieve]
15. Hasson, A., Fainzilber, M., Gordon, D., Zlotkin, E., and Spira, M. E. (1993) Eur. J. Neurosci. 5, 56-64 [CrossRef][Medline] [Order article via Infotrieve]
16. Hillyard, D. R., Olivera, B. M., Woodward, S., Gray, W. R., Corpuz, G. P., Ramilo, C. A., and Cruz, L. J. (1989) Biochemistry 28, 358-361 [CrossRef][Medline] [Order article via Infotrieve]
17. Kanner, B. J. (1978) Biochemistry 17, 1207-1211 [CrossRef][Medline] [Order article via Infotrieve]
18. Kofman, O., Sherman, W. R., Katz, V., and Belmaker, R. H. (1993) Psychopharmacology. 110, 229-234 [CrossRef][Medline] [Order article via Infotrieve]
19. Loret, E. P., Soto del Valle, R. M., Mansuelle, P., Sampieri, F., and Rochat, H. (1994) J. Biol. Chem. 269, 16785-16788 [Abstract/Free Full Text]
20. Moczydlowski, E., Olivera, B. M., Gray, W. R., and Strichartz, G. R. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 5321-5325 [Abstract/Free Full Text]
21. Moskowitz, H., Herrmann, R., Zlotkin, E., and Gordon, D. (1994) Insect Biochem. Mol. Biol. 24, 13-19
22. Olivera, B. M., Rivier, J., Scott, J. C., Hillyard, D. R., and Cruz, L. J. (1991) J. Biol. Chem. 266, 22067-22070 [Free Full Text]
23. Pallaghy, P. K., Duggan, B. M., Pennington, M. W., and Norton, R. S. (1993) J. Mol. Biol. 234, 405-420 [CrossRef][Medline] [Order article via Infotrieve]
24. Peterson, G. L. (1977) Anal. Biochem. 83, 346-356 [CrossRef][Medline] [Order article via Infotrieve]
25. Ray, R., Morrow, C. S., and Catterall, W. A. (1978) J. Biol. Chem. 25, 7307-7313
26. Sabatier, J. M., Zerrouk, H., Darbon, H., Mabrouk, K., Benslimane, A., Rochat, H., Martine-Euclaire, M. F., and Van Rietschoten, J. (1993) Biochemistry 32, 2763-2770 [CrossRef][Medline] [Order article via Infotrieve]
27. Shon, K. J., Hasson, A., Spira, M. E., Cruz, L. J., Gray, W. R., and Olivera, B. M. (1994) Biochemistry 33, 11420-11425 [CrossRef][Medline] [Order article via Infotrieve]
28. Skalicky, J. J., Metzler, W. J., Ciesla, D. J., Galdes, A., and Pardi, A. (1993) Protein Sci. 2, 1591-1603 [Medline] [Order article via Infotrieve]
29. Stephan, M. M., Potts, J. F., and Agnew, W. S. (1994) J. Membr. Biol. 137, 1-8 [Medline] [Order article via Infotrieve]
30. Tamkun, M. M., and Catterall, W. A. (1981) Mol. Pharmacol. 19, 78-86 [Abstract/Free Full Text]
31. Terlau, H., Heinemann, S. H., Stuhmer, W., Push, M., Conti, F., Imoto, K., and Numa, S. (1991) FEBS Lett. 293, 93-96 [CrossRef][Medline] [Order article via Infotrieve]
32. Thomsen, W. J., and Catterall, W. A. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 10161-10165 [Abstract/Free Full Text]

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				M.-M. Zhang, B. R. Green, P. Catlin, B. Fiedler, L. Azam, A. Chadwick, H. Terlau, J. R. McArthur, R. J. French, J. Gulyas, et al. Structure/Function Characterization of {micro}-Conotoxin KIIIA, an Analgesic, Nearly Irreversible Blocker of Mammalian Neuronal Sodium Channels J. Biol. Chem., October 19, 2007; 282(42): 30699 - 30706. [Abstract] [Full Text] [PDF]

				J. Ekberg, A. Jayamanne, C. W. Vaughan, S. Aslan, L. Thomas, J. Mould, R. Drinkwater, M. D. Baker, B. Abrahamsen, J. N. Wood, et al. {micro}O-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits PNAS, November 7, 2006; 103(45): 17030 - 17035. [Abstract] [Full Text] [PDF]

				L. Cohen, N. Lipstein, and D. Gordon Allosteric interactions between scorpion toxin receptor sites on voltage-gated Na channels imply a novel role for weakly active components in arthropod venom FASEB J, September 1, 2006; 20(11): 1933 - 1935. [Abstract] [Full Text] [PDF]

				P. J. West, G. Bulaj, and D. Yoshikami Effects of {delta}-Conotoxins PVIA and SVIE on Sodium Channels in the Amphibian Sympathetic Nervous System J Neurophysiol, December 1, 2005; 94(6): 3916 - 3924. [Abstract] [Full Text] [PDF]

				W. Ulbricht Sodium Channel Inactivation: Molecular Determinants and Modulation Physiol Rev, October 1, 2005; 85(4): 1271 - 1301. [Abstract] [Full Text] [PDF]

				L. Volpon, H. Lamthanh, J. Barbier, N. Gilles, J. Molgo, A. Menez, and J.-M. Lancelin NMR Solution Structures of {delta}-Conotoxin EVIA from Conus ermineus That Selectively Acts on Vertebrate Neuronal Na+ Channels J. Biol. Chem., May 14, 2004; 279(20): 21356 - 21366. [Abstract] [Full Text] [PDF]

				J. Barbier, H. Lamthanh, F. Le Gall, P. Favreau, E. Benoit, H. Chen, N. Gilles, N. Ilan, S. H. Heinemann, D. Gordon, et al. A {delta}-Conotoxin from Conus ermineus Venom Inhibits Inactivation in Vertebrate Neuronal Na+ Channels but Not in Skeletal and Cardiac Muscles J. Biol. Chem., February 6, 2004; 279(6): 4680 - 4685. [Abstract] [Full Text] [PDF]

				T. Kohno, T. Sasaki, K. Kobayashi, M. Fainzilber, and K. Sato Three-dimensional Solution Structure of the Sodium Channel Agonist/Antagonist delta -Conotoxin TxVIA J. Biol. Chem., September 20, 2002; 277(39): 36387 - 36391. [Abstract] [Full Text] [PDF]

				S. Cestèle, R. B. Khalifa, M. Pelhate, H. Rochat, and D. Gordon [IMAGE]-Scorpion Toxins Binding on Rat Brain and Insect Sodium Channels Reveal Divergent Allosteric Modulations by Brevetoxin and Veratridine J. Biol. Chem., June 23, 1995; 270(25): 15153 - 15161. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fainzilber, M. Articles by Gordon, D. Search for Related Content PubMed PubMed Citation Articles by Fainzilber, M. Articles by Gordon, D. Social Bookmarking                      What's this?