Spider toxins affecting glutamate receptors: Polyamines in therapeutic neurochemistry

doi:10.1016/0163-7258(91)90012-B

Pharmacology & Therapeutics

Volume 52, Issue 2, November 1991, Pages 245-268

https://doi.org/10.1016/0163-7258(91)90012-B Get rights and content

Abstract

Polyamine amide toxins obtained from venoms of spiders and wasps interact selectively with ionotropic glutamate receptors (GLU-R) of vertebrate central nervous systems. The sites and modes of action of these polyamine amide toxins are reviewed with particular reference to their structure-activity relationships. Qualitatively, their effects on GLU-R are identical to those exerted by polyamines such as spermine, but the polyamine amides are more potent. These compounds (a) potentiate and (b) antagonize GLU-R, the latter arising through open channel block. For the $N- methyl - D - aspartate$ receptor this non-competitive antagonism probably arises through binding of toxin to the Mg²⁺ site(s) located in the channel gated by this receptor. Similarities and differences between GLU-R in vertebrates and in invertebrates with respect to their interactions with polyamines and polyamine amide toxins are discussed. In both groups the low specificity of these compounds is illustrated by their antagonism at nicotinic acetylcholine receptors in addition to GLU-R. Electrophysiological studies, including those employing Xenopus oocytes, are reviewed and future prospects for the use of polyamine amides in therapy are discussed.

References (182)

M.E. Adams et al.
Structures and biological activities of three synaptic antagonists from orb weaver spider venom
Biochem. biophys. Res. Commun.
(1987)
M.E. Adams et al.
ω-Agatoxins: Novel calcium channel antagonists of two subtypes from funnel web spider (Agelenopsis aperta) venom
J. Biol. Chem.
(1990)
V.L. Arvanov et al.
Effect of ouabain on volume and chemosensitivity of Xenopus oocytes injected with rat brain mRNA
Neurosci. Lett.
(1991)
J.H. Ashe et al.
Argiotoxin-636 blocks excitatory synaptic transmission in rat hippocampal CA pyramidal neurons
Brain Res.
(1989)
E.A. Barnard et al.
The non-NMDA receptors: Types, protein structure and molecular biology
TIPS
(1990)
A. Bateman et al.
Postsynaptic block of a glutamatergic synapse by low molecular weight fractions of spider venom
Brain Res.
(1985)
P. Brackley et al.
Spermine and philanthotoxin potentiate excitatory amino acid responses of Xenopus oocytes injected with rat and chick brain RNA
Neurosci. Lett.
(1990)
M. Bruce et al.
Structure-activity relationships of analogues of the wasp toxin philanthotoxin: Non-competitive antagonists of quisqualate receptors
Toxicon
(1990)
P. Brundell et al.
Quisqualate-sensitive glutamate receptors of the locust Schistocerca gregaria are antagonised by intracellularly-applied philanthotoxin and spermine
Neurosci. Lett.
(1991)
T. Budd et al.
Isolation and characterisation of glutamate receptor antagonists from venoms of orb-web spiders
Brain Res.
(1988)

B.W. Bycroft et al.

Invertebrate pharmacological assay of novel potent glutamate antagonists: Acylated spermines

Eur. J. Pharmac.

(1990)

B.W. Bycroft et al.

Natural and synthetic polyamine derivatives as antagonists of glutamate receptors: An emerging structure/activity profile

Eur. J. Pharmac.

(1990)

R.B. Clark et al.

Block of locust muscle glutamate receptors by δ-philanthotoxin occurs after receptor activations

Brain Res.

(1982)

C.R. Diniz et al.

The purification and amino acid sequence of the lethal neurotoxin Tx1 from the venom of the Brazilian ‘armed’ spider Photoneutria nigriventer

FEBS Lett.

(1990)

S.L. Early et al.

Presence of proteins and glutamate as major constituents of the venom of the spider Araneus gemma

Toxicon

(1987)

A.C. Foster et al.

Acidic amino acid binding sites in mammalian neuronal membranes; their characteristics and relationship to synaptic receptors

Brain Res. Rev.

(1984)

Ch. Franke et al.

Liquid filament switch for ultra-fast exchanges of solutions at excised patches of synaptic membrane of crayfish muscle

Neurosci. Lett.

(1987)

D. Giles et al.

The effects of putative amino acid neurotransmitters on somata isolated from neurons of the locust central nervous system

Comp. Biochem. Physiol.

(1985)

R.A. Goodnow et al.

Synthesis of glutamate receptor antagonist philanthotoxin-433 (PhTX-433) and its analogs

Tetrahedron

(1990)

K.A.F. Gration et al.

Three types of glutamate receptor on functional membrane of locust muscle fibres

Brain Res.

(1979)

E.V. Grishin et al.

Isolation and structure analysis of components from venom of the spider Argiope lobata

Toxicon

(1989)

S.L. Guth et al.

Argiotoxin-636 blocks effects of $N- methyl - D - aspartate$ on lateral line of Xenopus laevis at concentrations which do not alter spontaneous or evoked neural activity

Life Sci.

(1990)

Y. Hashimoto et al.

Synthesis of spider toxin (JSTX-3) and its analogs

Tet. Lett.

(1987)

T. Himi et al.

Joro spider toxin (JSTX-3) and its analogue, 1-Naptthylacetylspermine (NpAc), inhibit glutamate toxicity on mice brain in vivo and in vitro

Eur. J. Pharmac.

(1990)

H. Ino et al.

Characterisation of binding sites for spider toxin ³H-NSTX-3, in the rat brain

Neurosci. Res. Commun.

(1990)

H. Jackson et al.

Spider toxins as tools for dissecting elements of excitatory amino acid transmission

Trends in Neurosci.

(1988)

V.J. Jasys et al.

The total synthesis of argiotoxins 636, 659 and 673

Tet. Lett.

(1988)

H. Karst et al.

Structure-activity relationships of philanthotoxins—ii. Effects on the glutamate gated ion channels of the locust muscle fibre membrane

Comp. Biochem. Physiol.

(1991)

N. Kawai et al.

Spider venom contains specific receptor blocker of glutamatergic synapses

Brain Res.

(1982)

C.J. Kerry et al.

Single channel studies of non-competitive antagonism of a quisqualate-sensitive glutamate receptor by argiotoxin-636—a fraction isolated from orb-web spider venom

Brain Res.

(1988)

T.J. Lea et al.

The site of action of ibotenic acid and the identification of two populations of glutamate receptors on insect muscle fibres

Comp. Gen. Pharmac.

(1973)

B.S. Meldrum et al.

Antiepileptic action of excitatory amino acid antagonists in the photosensitive baboon, Papio papio

Neurosci. Lett.

(1983)

T. Abe et al.

Effects of a spider toxin on the glutaminergic synapse of lobster muscle

J. Physiol.

(1983)

M.E. Adams

Synaptic ion channel toxins from spider venoms

N. Anis et al.

Structure-activity relationships of philanthotoxin analogs and polyamines on $N- methyl - D - asparate$ and nicotinic acetylcholine receptors

J. Pharmac. exp. Ther.

(1990)

S.M. Antonov et al.

Argiopine blocks glutamate-activated single-channel currents on crayfish muscle by two mechanisms

J. Physiol.

(1989)

Y. Aramaki et al.

Chemical characterisation of spider toxin, JSTX and NSTX

Y. Aramaki et al.

Chemical structure of Joro spider toxin (JSTX)

Biomed. Res.

(1987)

C.M. Armstrong

Interaction of tetraethylammonium ion derivatives with potassium channels of giant axons

J. gen. Physiol.

(1971)

T. Asami et al.

Acylpolyamines mimic the action of Joro spider toxin (JSTX) on crustacean muscle glutamate receptors

Biomed. Res.

(1989)

M.L.J. Ashford et al.

Effects of trimetaphan on locust muscle glutamate receptor

J. exp. Biol.

(1987)

M.L.J. Ashford et al.

Voltage-dependent block of locust muscle glutamate channels by chlorisondamine

J. exp. Biol.

(1988)

M.L.J. Ashford et al.

Enhancement of desensitization of quisqualate-type glutamate receptor by the dissociative anaesthetic ketamine

J. exp. Biol.

(1989)

E.A. Barnard et al.

Functional expression in the Xenopus oocyte of RNAs for receptors and ion channels

H. Benveniste et al.

Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

J. Neurochem.

(1984)

I.S. Blagbrough et al.

Mode of action of polyamine-derived glutamate antagonists

Pesticide Sci.

(1990)

I.S. Blagbrough et al.

Philanthotoxin-343—an analogue of a toxin from Philanthus triangulum: A practical synthesis of a potent glutamate antagonist

J. Pharm. Pharmac.

(1989)

I.S. Blagbrough et al.

Low molecular weight spider venom toxins isolated from Argiope and Araneus: Potent antagonists of glutamatergic transmission

J. Pharm. Pharmac.

(1989)

I.S. Blagbrough et al.

Invertebrate pharmacological assay of novel, potent glutamate antagonists: Acylated spermines

Pesticide Sci.

(1990)

I.S. Blagbrough et al.

Spider toxin analogues: Structure-activity studies

Pesticide Sci.

(1990)

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Spider toxins affecting glutamate receptors: Polyamines in therapeutic neurochemistry

Abstract

Biochem. biophys. Res. Commun.

J. Biol. Chem.

Neurosci. Lett.

Brain Res.

TIPS

Brain Res.

Neurosci. Lett.

Toxicon

Neurosci. Lett.

Brain Res.

Eur. J. Pharmac.

Eur. J. Pharmac.

Brain Res.

FEBS Lett.

Toxicon

Brain Res. Rev.

Neurosci. Lett.

Comp. Biochem. Physiol.

Tetrahedron

Brain Res.

Toxicon

Life Sci.

Tet. Lett.

Eur. J. Pharmac.

Neurosci. Res. Commun.

Trends in Neurosci.

Tet. Lett.

Comp. Biochem. Physiol.

Brain Res.

Brain Res.

Comp. Gen. Pharmac.

Neurosci. Lett.

Effects of a spider toxin on the glutaminergic synapse of lobster muscle

J. Physiol.

Synaptic ion channel toxins from spider venoms

Structure-activity relationships of philanthotoxin analogs and polyamines on N-methyl-D-asparate and nicotinic acetylcholine receptors

J. Pharmac. exp. Ther.

Argiopine blocks glutamate-activated single-channel currents on crayfish muscle by two mechanisms

J. Physiol.

Chemical characterisation of spider toxin, JSTX and NSTX

Chemical structure of Joro spider toxin (JSTX)

Biomed. Res.

Interaction of tetraethylammonium ion derivatives with potassium channels of giant axons

J. gen. Physiol.

Acylpolyamines mimic the action of Joro spider toxin (JSTX) on crustacean muscle glutamate receptors

Biomed. Res.

Effects of trimetaphan on locust muscle glutamate receptor

J. exp. Biol.

Voltage-dependent block of locust muscle glutamate channels by chlorisondamine

J. exp. Biol.

Enhancement of desensitization of quisqualate-type glutamate receptor by the dissociative anaesthetic ketamine

J. exp. Biol.

Functional expression in the Xenopus oocyte of RNAs for receptors and ion channels

Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

J. Neurochem.

Mode of action of polyamine-derived glutamate antagonists

Pesticide Sci.

Philanthotoxin-343—an analogue of a toxin from Philanthus triangulum: A practical synthesis of a potent glutamate antagonist

J. Pharm. Pharmac.

Low molecular weight spider venom toxins isolated from Argiope and Araneus: Potent antagonists of glutamatergic transmission

J. Pharm. Pharmac.

Invertebrate pharmacological assay of novel, potent glutamate antagonists: Acylated spermines

Pesticide Sci.

Spider toxin analogues: Structure-activity studies

Pesticide Sci.

Structure-activity relationships of philanthotoxin analogs and polyamines on $N- methyl - D - asparate$ and nicotinic acetylcholine receptors