A highly potent and selective N-methyl-D-aspartate receptor antagonist from the venom of the Agelenopsis aperta spider.
Agatoxin-489, extracted from the venom of the Agelenopsis aperta spider, was studied on acutely isolated perfused hippocampal neurons of rat using the concentration clamp technique. Agatoxin-489 proved to be a selective N-methyl-D-aspartate antagonist; responses to applications of N-methyl-D-aspartate or L-aspartate were blocked by concentrations of agatoxin-489 ranging between 0.1 nM and 1 microM, while responses to kainate were not affected by agatoxin-489 at concentrations up to 10 microM. The actions of agatoxin-489 against responses to N-methyl-D-aspartate or L-aspartate were use- and voltage-dependent, being less pronounced with an increase in the holding potential from -100 to -30 mV. The action of agatoxin-489 could be completely or partially reversed only after washout in the presence of an N-methyl-D-aspartate agonist. The washout was more effective at positive membrane potentials ranging from 0 to +20 mV. These results imply that the spider toxin agatoxin-489, like dizocilpine, is a potent and selective N-methyl-D-aspartate antagonist which preferentially interacts with activated N-methyl-D-aspartate receptors and/or open N-methyl-D-aspartate-activated ionic channels.
Department of Physico-Chemical Biology of Cellular Membranes, A. A. Bogomoletz Institute of Physiology, Academy of Sciences of the Ukraine, Kiev.
N I
NI
Kiskin
I V
IV
Chizhmakov
Tsyndrenko AYa
A L
AL
Mueller
H
H
Jackson
O A
OA
Krishtal
D060848:Agatoxins; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D011073:Polyamines / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013112:Spiders
D060848:Agatoxins; D005971:Glutamates; D009498:Neurotoxins; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C076532:agatoxin-489; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D007608:Kainic Acid