μ-Conotoxin SmIIIA, a Potent Inhibitor of Tetrodotoxin-Resistant Sodium Channels in Amphibian Sympathetic and Sensory Neurons

West, Peter J.; Bułaj, Grzegorz; Garrett, James E.; Olivera, Baldomero M.; Yoshikami, Doju

doi:10.1021/bi0265628

Cited by 81 publications

(103 citation statements)

References 28 publications

(48 reference statements)

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“…Off-rate constants (k off values) were determined from single-exponential fits of peak I Na following toxin washout; observed rate constants (k obs values) were obtained by single exponential fits of I Na following toxin addition and on-rate constants (k on values) were obtained from slopes of k obs versus [toxin], all as reported previously (West et al 2002). In particular instances (see the text immediately following), the time course of the recovery of I Na following toxin washout was biphasic and the recovery was fit to a double-exponential curve as previously reported ).…”

Section: Discussionmentioning

confidence: 99%

“…Experiments with: 1) these congeners as well as possible synthetic derivatives of both STX and TTX (good progress in guanidinium alkaloid syntheses is promising in this regard; Andresen and Du Bois 2009; Mulcahy and Du Bois 2008;Nishikawa et al 2004;Sato et al 2008); 2) close relatives of KIIIA, such as the -conotoxins SIIIA and SmIIIA (Bulaj et al 2005;West et al 2002); and 3) mutants of the channel, such as Na V 1.2[F385C] ), should advance our understanding of the mechanism of action of guanidinium alkaloids and -conopeptides that target site 1 of VGSCs. Furthermore, if active, covalently linked alkaloid-peptide adducts can be synthesized, these should provide insights into the arrangement of the units when bound to site 1, as well as also serve as second-generation ligands for sodium channels.…”

Section: Structural Models Of Alkaloid and Peptide Docked At The Outementioning

confidence: 99%

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Cooccupancy of the Outer Vestibule of Voltage-Gated Sodium Channels by μ-Conotoxin KIIIA and Saxitoxin or Tetrodotoxin

Zhang¹,

Gruszczyński

Walewska³

et al. 2010

Journal of Neurophysiology

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of the outer vestibule of voltage-gated sodium channels by -conotoxin KIIIA and saxitoxin or tetrodotoxin. J Neurophysiol 104: 88 -97, 2010. First published April 2, 2010 doi:10.1152/jn.00145.2010. The guanidinium alkaloids tetrodotoxin (TTX) and saxitoxin (STX) are classic ligands of voltage-gated sodium channels (VGSCs). Like TTX and STX, -conotoxin peptides are pore blockers but with greater VGSC subtype selectivity. -Conotoxin KIIIA blocks the neuronal subtype Na V 1.2 with nanomolar affinity and we recently discovered that KIIIA and its mutant with one fewer positive charge, KIIIA[K7A], could act synergistically with TTX in a ternary peptide·TTX·Na V complex. In the complex, the peptide appeared to trap TTX in its normal binding site such that TTX could not readily dissociate from the channel until the peptide had done so; in turn, the presence of TTX accelerated the rate at which peptide dissociated from the channel. In the present study we examined the inhibition of Na V 1.2, exogenously expressed in Xenopus oocytes, by STX (a divalent cation) and its sulfated congener GTX2/3 (with a net ϩ1 charge). Each could form a ternary complex with KIIIA and Na V 1.2, as previously found with TTX (a monovalent cation), but only when STX or GTX2/3 was added before KIIIA. The KIIIA·alkaloid·Na V complex was considerably less stable with STX than with either GTX2/3 or TTX. In contrast, ternary KIIIA[K7A]·alkaloid·Na V complexes could be formed with either order of ligand addition and were about equally stable with STX, GTX2/3, or TTX. The most parsimonious interpretation of the overall results is that the alkaloid and peptide are closely apposed in the ternary complex. The demonstration that two interacting ligands ("syntoxins") occupy adjacent sites raises the possibility of evolving a much more sophisticated neuropharmacology of VGSCs. I N T R O D U C T I O NVoltage-gated sodium channels (VGSCs) are responsible for the upstroke of action potentials in excitable cells. Tetrodotoxin (TTX) and saxitoxin (STX) are guanidinium alkaloids (Fig. 1A) that block six of the nine isoforms of the pore-bearing ␣-subunit of mammalian VGSCs with K d values in the nanomolar range (Catterall et al. 2005). -Conotoxins, which also block VGSCs, are peptides of 16 to 25 residues, including six cysteines that form a characteristic disulfide framework (see Fig. 1B) (Terlau and Olivera 2004). In contrast to the promiscuity of TTX and STX, GIIIA, the best-studied -conotoxin, is significantly more potent against the skeletal muscle subtype of channel Na V 1.4 (half-maximal inhibitory concentration [IC 50 ] ϭ 19 nM), than other TTX-sensitive subtypes, such as brain We recently discovered -conotoxins KIIIA and SIIIA, which block Na V 1.2 with higher affinity than Na V 1.4 (Bulaj et al. 2005;Yao et al. 2008;Zhang et al. 2007). Single-channel analyses of brain VGSCs in planar lipid bilayers showed that KIIIA produced only a partial block (Zhang et al. 2007). In saturating concentrations of KIIIA or its mutant KIIIA[K7A], a residual sodium curre...

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Section: Discussionmentioning

confidence: 99%

Section: Structural Models Of Alkaloid and Peptide Docked At The Outementioning

confidence: 99%

Cooccupancy of the Outer Vestibule of Voltage-Gated Sodium Channels by μ-Conotoxin KIIIA and Saxitoxin or Tetrodotoxin

Zhang¹,

Gruszczyński

Walewska³

et al. 2010

Journal of Neurophysiology

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“…A new -conotoxin that has neuronal subtype specificity for voltage-gated sodium channels was recently reported; this peptide, -conotoxin SmIIIA from Conus stercusmuscarum, has several distinctive sequence features (see Table 1) (186). Uniquely among Na channel ligands, this peptide inhibited most TTX-resistant Na current irreversibly in voltage-clamped dissociated neurons from frog sympathetic and dorsal root ganglia.…”

Section: B Na Channel-targeted Toxinsmentioning

confidence: 99%

ConusVenoms: A Rich Source of Novel Ion Channel-Targeted Peptides

Terlau

Olivera

2004

Physiological Reviews

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828

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Terlau, Heinrich, and Baldomero M. Olivera. Conus Venoms: A Rich Source of Novel Ion Channel-Targeted Peptides. Physiol Rev 84: 41–68, 2004; 10.1152/physrev.00020.2003.—The cone snails (genus Conus) are venomous marine molluscs that use small, structured peptide toxins (conotoxins) for prey capture, defense, and competitor deterrence. Each of the 500 Conus can express ∼100 different conotoxins, with little overlap between species. An overwhelming majority of these peptides are probably targeted selectively to a specific ion channel. Because conotoxins discriminate between closely related subtypes of ion channels, they are widely used as pharmacological agents in ion channel research, and several have direct diagnostic and therapeutic potential. Large conotoxin families can comprise hundreds or thousands of different peptides; most families have a corresponding ion channel family target (i.e., ω-conotoxins and Ca channels, α-conotoxins and nicotinic receptors). Different conotoxin families may have different ligand binding sites on the same ion channel target (i.e., μ-conotoxins and δ-conotoxins to sites 1 and 6 of Na channels, respectively). The individual peptides in a conotoxin family are typically each selectively targeted to a diverse set of different molecular isoforms within the same ion channel family. This review focuses on the targeting specificity of conotoxins and their differential binding to different states of an ion channel.

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“…Currently 12 -conotoxins have been identified from nine species of fish hunting cone snails (Table 1). -Conotoxins GIIIA, GIIIB, and GIIIC from Conus geographus selectively target the skeletal muscle Na v 1.4, PIIIA from Conus purpurasence (12)(13)(14) and TIIIA from Conus tulipa (15) target Na v 1.2 and 1.4, and -conotoxins SmIIIA from Conus stercusmuscsarum (16,17), SIIIA from Conus striatus (18,19), and KIIIA from Conus kinoshitai (18) target amphibian TTX-R sodium channels. More recently, KIIIA has also been shown to inhibit TTX-S sodium channels in mouse DRG and rat TTX-S sodium channels expressed in Xenopus oocytes (20).…”

mentioning

confidence: 99%

Neuronally Selective μ-Conotoxins from Conus striatus Utilize an α-Helical Motif to Target Mammalian Sodium Channels

Schroeder

Ekberg

Nielsen³

et al. 2008

Journal of Biological Chemistry

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μ-Conotoxin SmIIIA, a Potent Inhibitor of Tetrodotoxin-Resistant Sodium Channels in Amphibian Sympathetic and Sensory Neurons

Cited by 81 publications

References 28 publications

Cooccupancy of the Outer Vestibule of Voltage-Gated Sodium Channels by μ-Conotoxin KIIIA and Saxitoxin or Tetrodotoxin

Cooccupancy of the Outer Vestibule of Voltage-Gated Sodium Channels by μ-Conotoxin KIIIA and Saxitoxin or Tetrodotoxin

ConusVenoms: A Rich Source of Novel Ion Channel-Targeted Peptides

Neuronally Selective μ-Conotoxins from Conus striatus Utilize an α-Helical Motif to Target Mammalian Sodium Channels

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