.alpha.-Conotoxin EI, A New Nicotinic Acetylcholine Receptor Antagonist with Novel Selectivity

Js, Martinez; Olivera, B.M.; Wr, Gray; Ag, Craig; Dr, Groebe; Sn, Abramson; McIntosh, J. M.

doi:10.1021/bi00044a030

Cited by 103 publications

(131 citation statements)

References 22 publications

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“…A consistent finding in this study, based on analysis of individual C. striatus, is that the peptide composition of DV is significantly more complex than that of IV, in agreement with previous studies Martinez et al, 1995). In general, IV appears to contain a substantially simplified subset of the DV peptides (Fig.·2).…”

Section: Differences In Composition Of Duct Venom and Injected Venomsupporting

confidence: 92%

“…The results of this study imply that novel regulatory mechanisms exist to select specific venom peptides for injection into prey. 2874 studies, venom expelled through the radular tooth during feeding behavior was collected by a simple 'milking' procedure (Bingham et al, 2005Hopkins et al, 1995;Martinez et al, 1995;Shon et al, 1997Shon et al, , 1995Teichert et al, 2004;Walker et al, 1999), and analysis indicated that this injected venom (IV) was not identical to DV from the same species Martinez et al, 1995). Venom milking is thus advantageous because it provides the biologically relevant peptides used to subdue prey and does not require sacrificing the snail.…”

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confidence: 99%

“…In studies employing IV (Bingham et al, 2005Hopkins et al, 1995;Martinez et al, 1995;Shon et al, 1997Shon et al, , 1995Teichert et al, 2004;Walker et al, 1999), the samples were pooled from multiple snails, and therefore the degree of intraspecific variation could not be assessed. Intraspecific variation has been examined using DV from individual snails; however these studies have produced conflicting results.…”

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confidence: 99%

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Intraspecific variation of venom injected by fish-hunting Conussnails

Jakubowski

Kelley

Sweedler

et al. 2005

Journal of Experimental Biology

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SUMMARY Venom peptides from two species of fish-hunting cone snails (Conus striatus and Conus catus) were characterized using microbore liquid chromatography coupled with matrix-assisted laser desorption/ionization-time of flight-mass spectrometry and electrospray ionization-ion trap-mass spectrometry. Both crude venom isolated from the venom duct and injected venom obtained by milking were studied. Based on analysis of injected venom samples from individual snails, significant intraspecific variation (i.e. between individuals) in the peptide complement is observed. The mixture of peptides in injected venom is simpler than that in the crude duct venom from the same snail, and the composition of crude venom is more consistent from snail to snail. While there is animal-to-animal variation in the peptides present in the injected venom, the composition of any individual's injected venom remains relatively constant over time in captivity. Most of the Conus striatus individuals tested injected predominantly a combination of two neuroexcitatory peptides (s4a and s4b),while a few individuals had unique injected-venom profiles consisting of a combination of peptides, including several previously characterized from the venom duct of this species. Seven novel peptides were also putatively identified based on matches of their empirically derived masses to those predicted by published cDNA sequences. Profiling injected venom of Conus catus individuals using matrix-assisted laser desorption/ionization-time of flight-mass spectrometry demonstrates that intraspecific variation in the mixture of peptides extends to other species of piscivorous cone snails. The results of this study imply that novel regulatory mechanisms exist to select specific venom peptides for injection into prey.

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Section: Differences In Composition Of Duct Venom and Injected Venomsupporting

confidence: 92%

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confidence: 99%

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confidence: 99%

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Intraspecific variation of venom injected by fish-hunting Conussnails

Jakubowski

Kelley

Sweedler

et al. 2005

Journal of Experimental Biology

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“…The ␣3/5-conotoxins are selective for the muscle-type nAChR, while most ␣4/7-and ␣4/6-conotoxins are selective for neuronal nAChRs. An exception is the ␣4/7-conotoxin EI, which binds to the ␣/␦ interface of the muscle-type nAChR (9). The ␣4/3-type characterized by ImI is ␣7-selective (10).…”

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confidence: 99%

Isolation, Structure, and Activity of GID, a Novel α4/7-Conotoxin with an Extended N-terminal Sequence

Nicke¹,

Loughnan²,

Millard³

et al. 2003

Journal of Biological Chemistry

127

152

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Using assay-directed fractionation of Conus geographus crude venom, we isolated ␣-conotoxin GID, which acts selectively at neuronal nicotinic acetylcholine receptors (nAChRs). Unlike other neuronally selective ␣-conotoxins, ␣-GID has a four amino acid N-terminal tail, ␥-carboxyglutamate (Gla), and hydroxyproline (O) residues, and lacks an amidated C terminus. GID inhibits ␣7 and ␣3␤2 nAChRs with IC 50 values of 5 and 3 nM, respectively and is at least 1000-fold less potent at the ␣1␤1␥␦, ␣3␤4, and ␣4␤4 combinations. GID also potently inhibits the ␣4␤2 subtype (IC 50 of 150 nM). Deletion of the N-terminal sequence (GID⌬1-4) significantly decreased activity at the ␣4␤2 nAChR but hardly affected potency at ␣3␤2 and ␣7 nAChRs, despite enhancing the off-rates at these receptors. In contrast, Arg 12 contributed to ␣4␤2 and ␣7 activity but not to ␣3␤2 activity. The threedimensional structure of GID is well defined over residues 4 -19 with a similar motif to other ␣-conotoxins. However, despite its influence on activity, the tail appears to be disordered in solution. Comparison of GID with other ␣4/7-conotoxins which possess an NN(P/O) motif in loop II, revealed a correlation between increasing length of the aliphatic side-chain in position 10 (equivalent to 13 in GID) and greater ␣7 versus ␣3␤2 selectivity. Neuronal nicotinic acetylcholine receptors (nAChR)1 represent important targets for the development of novel drugs for the treatment of pain and various disorders of the central nervous system (1). To date, eight ␣ and three ␤ subunits (␣2-␣7, ␣9, ␣10, ␤2-␤4) of the nAChRs have been cloned from sensory and neuronal mammalian cells (2-4). For the ␣7 and ␣9 subunits, it has been shown that they need no additional subunits to form functional ion channels upon heterologous expression. All other ␣ subunits, however, require at least the co-expression of one ␤ subunit, or another ␣ subunit in the case of ␣10. Ternary combinations of two different ␣ and one ␤ subunit or two different ␤ and one ␣ subunit, and even quaternary combinations have been described (5, 6). This diversity of subunit combinations has the potential to generate a wide range of receptor subtypes with different pharmacological and functional properties. To help unravel which native neuronal nAChR subunit combinations are responsible for specific physiological functions, additional selective inhibitors are required.Conotoxins are small disulfide-rich peptides from the venom of the predatory marine snails of the genus Conus. These miniproteins have proved to be valuable tools for investigating the structure and function of ligand-and voltage-gated ion channels. ␣-Conotoxins are competitive antagonists of acetylcholine (ACh) binding to the nAChR (7). The ␣-conotoxins described so far are among the most selective inhibitors to be identified (Fig.

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“…The ␣-conotoxins PnIA and PnIB from a molluschunting cone snail, Conus pennaceus (8), and ImI from a wormhunting cone snail, Conus imperialis (9) share a similar cysteine framework to ␣-conotoxins from fish-hunting cones, but have a different sequence pattern and target the neuronal subtypes of the nAChR. The ␣-conotoxins MII and EI from fish-hunting cones resemble the latter group in sequence pattern, but EI targets the muscle-type nAChR (10,11). The new ␣A-conotoxin class, which includes PIVA isolated from the fishhunting Conus purpurascens, contains atypical sequences and a novel cysteine framework (12).…”

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confidence: 99%

α-Conotoxin EpI, a Novel Sulfated Peptide from Conus episcopatusThat Selectively Targets Neuronal Nicotinic Acetylcholine Receptors

Loughnan

Bond

Atkins

et al. 1998

Journal of Biological Chemistry

109

100

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We have isolated and characterized ␣-conotoxin EpI, a novel sulfated peptide from the venom of the molluscivorous snail, Conus episcopatus. The peptide was classified as an ␣-conotoxin based on sequence, disulfide connectivity, and pharmacological target. EpI has homology to sequences of previously described ␣-conotoxins, particularly PnIA, PnIB, and ImI. However, EpI differs from previously reported conotoxins in that it has a sulfotyrosine residue, identified by amino acid analysis and mass spectrometry. Native EpI was shown to coelute with synthetic EpI. The peptide sequence is consistent with most, but not all, recognized criteria for predicting tyrosine sulfation sites in proteins and peptides.

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.alpha.-Conotoxin EI, A New Nicotinic Acetylcholine Receptor Antagonist with Novel Selectivity

Cited by 103 publications

References 22 publications

Intraspecific variation of venom injected by fish-hunting Conussnails

Intraspecific variation of venom injected by fish-hunting Conussnails

Isolation, Structure, and Activity of GID, a Novel α4/7-Conotoxin with an Extended N-terminal Sequence

α-Conotoxin EpI, a Novel Sulfated Peptide from Conus episcopatusThat Selectively Targets Neuronal Nicotinic Acetylcholine Receptors

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