Structure of saxitoxin

Schantz, Edward J.; Ghazarossian, Vartan E.; Schnoes, Heinrich K.; Strong, F. M.; Springer, James P.; Pezzanite, John O.; Clardy, Jon

doi:10.1021/ja00838a045

Cited by 276 publications

(103 citation statements)

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“…The numbering refers to Fig. 1, taken from Schantz et al (1975). Since these hydrogens are exchangeable, it is possible to label saxitoxin with a new method using exchange from tritiated water (T20).…”

Section: Methodsmentioning

confidence: 99%

A new method for labelling saxitoxin and its binding to non-myelinated fibres of the rabbit vagus, lobster walking leg, and garfish olfactory nerves.

Ritchie¹,

Rogart²,

Strichartz³

1976

The Journal of Physiology

195

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SUMMARY 1.A new method of labelling saxitoxin (STX) is described, based on transfer of tritium from tritiated water to the toxin.2. The radiochemical purity of the labelled toxin has been directly determined, rather than being based on indirect biochemical means, as in previous experiments with Wilzbach-labelled STX and TTX.3. The specific activity of the labelled toxin, 66 d.p.m.f-mole-1, corresponds with one tritium atom per molecule STX, an improvement of about 300-fold over other means of labelling TTX and STX.4. The binding of this toxin to rabbit, lobster and garfish olfactory nerve fibres has been re-examined. 5. The density of sodium channels calculated on the basis of the binding of the toxin is about four to six-times the values previously reported.

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Section: Methodsmentioning

confidence: 99%

A new method for labelling saxitoxin and its binding to non-myelinated fibres of the rabbit vagus, lobster walking leg, and garfish olfactory nerves.

Ritchie¹,

Rogart²,

Strichartz³

1976

The Journal of Physiology

195

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“…The k off values for the bimolecular complex KIIIA[K7A]·Na V and the ternary complexes KIIIA·TTX·Na V and KIIIA[K7A]·TTX·Na V were similar; in contrast, the k off value for KIIIA·Na V was 10-fold smaller, indicating that the presence of TTX decreased the stability of KIIIA·TTX·Na V . We hypothesized that TTX and peptide bound abutting microsites (Olivera et al 1991), within the greater confines of a macrosite synonymous with neurotoxin receptor site 1 designated by Catterall (Catterall 1980;Cestele and Catterall 2000).In this report we tested STX, which has two positive charges (Bordner et al 1975;Schantz et al 1975), in contrast to TTX's single charge (Hille 1975), and GTX2/3, a naturally occurring STX congener with a net ϩ1 charge (Fig. 1A).…”

mentioning

confidence: 94%

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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“…PSP is caused by planktonic dinoflagellates of the genera Alexandrium, Gymnodinium and Peridinium. These microscopic phytoplankton produce paralytic shellfish toxins (PST), a group of highly potent neurotoxic alkaloids among which saxitoxin was the first to be discovered (Schantz et al 1975). PST may cascade through the food web and intoxicate higher trophic levels and occasional mass mortalities of marine mammals and seabirds have been attributed to PST (Landsberg 2002).…”

Section: Introductionmentioning

confidence: 99%

Copepods induce paralytic shellfish toxin production in marine dinoflagellates

Selander¹,

Thor

Toth³

et al. 2006

Proc. R. Soc. B.

176

208

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Among the thousands of unicellular phytoplankton species described in the sea, some frequently occurring and bloom-forming marine dinoflagellates are known to produce the potent neurotoxins causing paralytic shellfish poisoning. The natural function of these toxins is not clear, although they have been hypothesized to act as a chemical defence towards grazers. Here, we show that waterborne cues from the copepod Acartia tonsa induce paralytic shellfish toxin (PST) production in the harmful algal bloom-forming dinoflagellate Alexandrium minutum. Induced A. minutum contained up to 2.5 times more toxins than controls and was more resistant to further copepod grazing. Ingestion of non-toxic alternative prey was not affected by the presence of induced A. minutum. The ability of A. minutum to sense and respond to the presence of grazers by increased PST production and increased resistance to grazing may facilitate the formation of harmful algal blooms in the sea.

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Structure of saxitoxin

Cited by 276 publications

References 1 publication

A new method for labelling saxitoxin and its binding to non-myelinated fibres of the rabbit vagus, lobster walking leg, and garfish olfactory nerves.

A new method for labelling saxitoxin and its binding to non-myelinated fibres of the rabbit vagus, lobster walking leg, and garfish olfactory nerves.

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

Copepods induce paralytic shellfish toxin production in marine dinoflagellates

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