When different cone snail peptides are injected into the CNS of vertebrates, they elicit diverse behaviors primarily because of their selectivity for specific receptor or ion channel subtypes. The subcellular context ...
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When different cone snail peptides are injected into the CNS of vertebrates, they elicit diverse behaviors primarily because of their selectivity for specific receptor or ion channel subtypes. The subcellular context of the highly localized targets (i,e, the presence of other cellular elements that are functionally linked to the targets of conopeptides) is another determinant of the elicited behavior, Recent studies have advanced our understanding of the mechanisms by which four conopeptides produce different behaviors in mice.
alpha-Conotoxin MII (CtxMII), a peptide toxin from the venom of the predatory cone snail Conus magus, displays an unusual nicotinic pharmacology. Specific binding of a radioiodinated derivative (I-125-alpha-CtxMII) wa...
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alpha-Conotoxin MII (CtxMII), a peptide toxin from the venom of the predatory cone snail Conus magus, displays an unusual nicotinic pharmacology. Specific binding of a radioiodinated derivative (I-125-alpha-CtxMII) was identified in brain region homogenates and tissue sections. Quantitative autoradiography indicated that I-125-alpha-CtxMII binding sites have an unique pharmacological profile and distribution in mouse brain, being largely confined to the superficial layers of the superior colliculus, nigrostriatal pathway, optic tract, olivary pretectal, and mediolateral and dorsolateral geniculate nuclei. Expression of alpha-CtxMII binding sites in the nigrostriatal pathway, combined with evidence for alpha-CtxMII-sensitivity of nicotine-induced [H-3]dopamine release in rodent striatal preparations indicates that I-125-alpha-CtxMII binding nicotinic acetylcholine receptors are likely to be physiologically important. Unlabeled alpha-CtxMII potently (K-i < 3 nM) competed for a subset of [H-3]epibatidine binding sites in mouse brain homogenates, but weakly (IC50 > 10 mu M) interacted with I-125-alpha-bungarotoxin and (-)-[H-3]nicotine binding sites, confirming this compound's novel nicotinic pharmacology. Quantitative autoradiography revealed that alpha-CtxMII binds with high affinity at a subset of [H-3]epibatidine binding sites with relatively low cytisine affinity ("cytisine-resistant" sites), resolving [H-3]epibatidine binding into three different populations, each probably corresponding to a receptor subtype. The majority population seems to correspond to that which binds nicotine and cytisine with high affinity ("cytisine-sensitive" sites). Comparison of the cytisine-resistant population's distribution with that of alpha 3 subunit mRNA expression suggests that the fractions both more and less sensitive to alpha-CtxMII probably contain the alpha 3 subunit, perhaps in combination with different beta subunits.
Conantokin G (Con G) is a 17-amino-acid peptide antagonist of N-methyl-D-aspartate (NMDA) receptors isolated from the venom of the marine cone snail, Conus geographus. The mechanism of action of Con G has not been wel...
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Conantokin G (Con G) is a 17-amino-acid peptide antagonist of N-methyl-D-aspartate (NMDA) receptors isolated from the venom of the marine cone snail, Conus geographus. The mechanism of action of Con G has not been well defined;both competitive and noncompetitive interactions with the NMDA-binding site have been proposed. In this study the mechanism of action and subunit selectivity of Con G was examined in whole-cell voltage-clamp recordings from cultured neurons and in two electrode voltage-clamp recordings from Xenopus oocytes expressing recombinant NMDA receptors. Con G was a potent and selective antagonist of NMDA-evoked currents in murine cortical neurons (IC50 = 480 nM). The slow onset of Con G block could be prevented by coapplication with high concentrations of NMDA or of the competitive antagonist (RS)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid. Furthermore, in oocytes expressing NR1a/NR2B receptors, Con G produced a rightward shift in the concentration-response curve for NMDA, providing support for a competitive interaction with the NMDA-binding site. Con G produced an apparent noncompetitive shift in the concentration-response curve for spermine potentiation of NMDA responses, but this was due to spermine-induced enhancement of Con G block. Spermine produced a similar enhancement of DL-2-amino-S-phosphopentanoic acid block. Finally, Con G selectively blocked NMDA receptors containing the NR2B subunit. These results demonstrate that Con G is a subunit-specific competitive antagonist of NMDA receptors. The unique subunit selectivity profile of Con G may explain its favorable in vivo profile compared with nonselective NMDA antagonists.
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