Nephilatoxins

Definition
Nephilatoxins are Joro spider toxins (JSTX) originally derived from Nephila clavata. These toxins have been found to block excitatory postsynaptic potentials and glutamate-evoked responses in the neuromuscular synapse of crustacea, the squid giant synapse and the mammalian brain synapse1.

Related peptides
JSTX from Nephila clavata, NSTX from Nephila maculata, and argiopine (argiotoxin) from Argiope lobata, act postsynaptically on glutamate receptors. These toxins share a common structure of a phenolic moiety connected to a polyamine. Chemical synthesis of these low molecular weight toxins has enabled morphological and biochemical studies of the glutamate receptors2.

Discovery
The acylpolyaminetoxins constitute a common class of neuroblockers, occurring as complex mixtures of similar compounds containing an aromatic group at the end of a polyamine chain in the venoms of spiders. They were first described by Kawai et al in 1982 and the first structures were characterized from the venom of Nephila masculata by Aramaki et al in 1986 3.

Structural Characteristics
Structures of the toxins (JSTXs, NSTXs) of spiders belonging to the genus Nephila were determined and it was found that a unique 2,4-dihydroxyphenylacetyl asparaginyl cadaverine part was conserved between all toxins, indicating that this part is intimately involved in the blocking activity1.These are polyamine peptides comprising an aryl L-asparaginyl residue and a polyamine chain attached to a number of cationic L-amino acids. The presence of an indole-3-acetyl or 6-hydroxy-indole-3-acetyl residue is a common feature of this family of neurotoxins4.

Mode of Action
The blocking action of Nephila clavata spider neurotoxin, or JSTX, on ionic currents activated by L-glutamate and its agonists when applied to the membrane of neurons isolated from the rat hippocampus was investigated using a concentration clamp technique. Crude JSTX venom was found to block L-glutamate-, quisqualate, and kainate-activated ionic currents induced by activating non-N-methyl-D-aspartate (non-NMDA) membrane receptors. Following the effects of JSTX, ionic currents activated by L-glutamate and its agonists declined to 34–36% of their initial value with no recovery during JSTX washout. It is postulated that JSTX interacts with chemically-operated non-NMDA ionic channels, blocking their transition into a number of their possible open states5.The 2,4 dihydroxyphenylacetyl asparagine in the toxin structure was responsible for suppressive action, while the remaining part containing a polyamine was related to the agonist binding site with the polycationic part enhancing the toxic activity6.

Functions
JSTX derived from Nephila clavata has been found to block excitatory postsynaptic potentials and glutamate-evoked responses in the neuromuscular synapse of crustacea, the squid giant synapse and the mammalian brain synapse1. Many kinds of venomous principles modulate physiological responses of mammalian signal transduction systems, on which they act selectively as enhancers, inhibitors or some other kind of effectors. These toxins become useful tools for physiological research7.

References
1.Kawai N and Nakajima T (1990). Characterization of Glutamate Receptor by Spider Toxin. Toxin Reviews, 9(2):203-223.
2.Kawai N (1991). Neuroactive Toxins of Spider Venoms. Toxin Reviews., 10(2):131-167
3.Palma MS, Itagaki Y, Fujita T, Naoki H, Nakajima T(1998). Structural characterization of a new acylpolyaminetoxin from the venom of Brazilian Garden Spider Nephilengys cruentata. Toxicon., 36(3):485-493.
4.Bycroft BW, Chan WC, Hone ND, Millington S, I. A. Nash IA. (1994). Synthesis of the Spider Toxins Nephilatoxin-9 and -11 by a Novel Solid-Phase Strategy. J. Am. Chem. Soc., 116(16)7415–7416.
5.Kiskin NI, Kliuchko EM, Kryshtal' OA, Tsyndrenko AIa, Akaike N. (1989). Blocking action of Nephila clavata spider toxin on ionic currents activated by glutamate and its agonists in isolated hippocampal neurons. Neirofiziologiia, 21(2):152-160.
6.Kawai N, Miwa A, Shimazaki K, Sahara Y, Robinson HP, Nakajima T(1991). Spider toxin and the glutamate receptors. Comp Biochem Physiol C., 98:87-95.
7.Terumi Nakajima. 2006. Nanoanalysis of the arthropod neuro-toxins. Proceedings of the Japan Academy, 82(8):297-310.