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At least 325 records · Page 18Linked to original sources
PubMed1995

New sodium channel-blocking conotoxins also affect calcium currents in Lymnaea neurons.

Two new conotoxins that affect both sodium and calcium currents have been characterized from the venom of Conus marmoreus, using direct assays on voltage-gated currents in caudodorsal neurons (CDC) of the freshwater snail Lymnaea stagnalis. The designations and amino acid sequences of the new toxins are MrVIA, ACRKKWEYCIVPIIGFIYCCPGLICGPFVCV, and MrVIB, ACSKKWEYCIVPILGFVYCCPGLICGPFVCV. Both toxins block voltage dependent sodium currents in snail neurons with ED50's of 0.1-0.2 microM. Effects are also observed on the fast-inactivating calcium current subtype in the CDC at > or = 1 microM. At concentrations of 1-5 microM, MrVIA acts as a calcium current agonist whereas MrVIB acts as a blocker. At higher doses both toxins block the fast-inactivating calcium current. Almost no effects of MrVIB are seen on the second (sustained kinetics) CDC calcium current subtype, while MrVIA also slightly blocks the sustained current. The calcium current block is rapidly reversible, whereas in contrast recovery of the sodium current requires extensive wash. MrVIA/B have the same cysteine framework as the omega- and delta-conotoxins and a high content of hydrophobic residues, in common with the delta-conotoxins. There is only one localized concentration of charged residues in MrVIA/B, in the first intercysteine loop. These two conotoxins provide unique probes for structure and function studies on voltage-gated sodium and L-type calcium channels. Their unusual cross-channel activity suggests they may represent an "intermediate" variant of conotoxin, in the diversification of one conotoxin structural family that selectively targets either sodium or calcium channels.

Amino Acid Sequence↗
PubMed2001

Delta-conotoxin structure/function through a cladistic analysis.

Delta-conotoxins are Conus peptides that inhibit inactivation of voltage-gated sodium channels. The suggestion that delta-conotoxins might be an essential component of the venoms of fish-hunting cone snails which rapidly immobilize their prey [Terlau, H., Shon, K., Grilley, M., Stocker, M., Stühmer, W., and Olivera, B. M. (1996) Nature 381, 148-151] has not been tested. On the basis of cDNA cloning, all of the fish-hunting Conus analyzed yielded at least one delta-conotoxin sequence. In addition, one delta-conotoxin isolated from the venom of Conus striatus had an amino acid sequence identical to that predicted from cDNA cloning. This new peptide exhibited properties of delta-conotoxins: it targeted sodium channels and potentiated action potentials by slowing channel inactivation. Homologous sequences of delta-conotoxins from two groups (clades) of related fish-hunting Conus species share consensus features but differ significantly from the two known delta-conotoxins from mollusc-hunting Conus venoms. Three large hydrophobic amino acids were conserved; analogues of the previously described delta-conotoxin PVIA with alanine substituted for the conserved amino acids F9 and I12 lost substantial biological activity. In contrast, both the T8A and K13A delta-conotoxin PVIA analogues, where substitutions were at nonconserved loci, proved to be biologically active. Taken together, our results indicate that a cladistic approach can identify amino acids critical for the activity of conotoxins and provide extensive information as to which amino acid substitutions can be made without significant functional consequences.

Action Potentials↗
PubMed1990

Diversity of Conus neuropeptides.

Conus venoms contain a remarkable diversity of pharmacologically active small peptides. Their targets are ion channels and receptors in the neuromuscular system. The venom of Conus geographus contains high-affinity peptides that act on voltage-sensitive calcium channels, sodium channels, N-methyl-D-aspartate (NMDA) receptors, acetylcholine receptors, and vasopressin receptors; many more peptides with still uncharacterized receptor targets are present in this venom. It now seems that the Conus species (approximately 500 in number) will each use a distinctive assortment of peptides and that the pharmacological diversity in Conus venoms may be ultimately comparable to that of plant alkaloids or secondary metabolites of microorganisms. The cone snails may generate this diverse spectrum of venom peptides by a "fold-lock-cut" synthetic pathway. These peptides are specific enough to discriminate effectively between closely related receptor subtypes and can be used for structure-function correlations.

Amino Acid Sequence↗
PubMed1988

Phylogenetic specificity of cholinergic ligands: alpha-conotoxin SI.

The alpha-conotoxins are small peptide neurotoxins from the venom of fish-hunting cone snails which block nicotinic acetylcholine receptors (nAChRs). We describe the purification, characterization, and chemical synthesis of a new alpha-conotoxin from Conus striatus, alpha-conotoxin SI. In contrast to other AChR ligands, alpha-SI discriminates between different vertebrate nAChRs. The sequence of alpha-conotoxin SI is Ile-Cys-Cys-Asn-Pro5-Ala-Cys-Gly-Pro-Lys10-Tyr-Ser-Cys-NH2. This sequence was confirmed by chemical synthesis. A des-Ile-alpha-SI derivative was also synthesized and is biologically active. Although alpha-conotoxin SI is highly homologous to previously described alpha-conotoxins, it has one noteworthy sequence feature which may account for its novel biological specificity. In all other alpha-conotoxins, there is a positively charged amino acid at residue 9; in alpha-conotoxin SI, this is replaced by proline. The discovery that different alpha-conotoxins can vary by orders of magnitude in their apparent affinity for different vertebrate receptors demonstrates that alpha-conotoxins will be useful probes for investigating phylogenetic differences between vertebrate nAChRs.

Amino Acid Sequence↗
PubMed2004

A novel structural class of toxins: the methionine-rich peptides from the venoms of turrid marine snails (Mollusca, Conoidea).

The objective of this investigation was to purify and characterize polypeptides from the venom ducts of the turrid snails Polystira albida and Gemmula periscelida (superfamily: Conoidea, family: Turridae), collected in Mexican waters. Venoms of other groups in the superfamily (family: Conidae, genus: Conus) have peptide toxins ('conotoxins'), but no venom components have been characterized from any turrid species. Crude venoms were fractionated using reversed-phase high performance liquid chromatography, and one major component from each venom was characterized. In contrast to most conotoxins, the polypeptides characterized contain a high proportion of Met, Tyr and Arg residues, and few, if any, Cys residues. The two peptides had some regions of homology, but were not significantly similar to other peptides. Both peptides are predicted to contain alpha-helical structures, and the peptide from P. albida is predicted to form a coiled-coil motif. This structural motif could provide conformational stability for these turrid venom components ("turritoxins"), which in the case of conotoxins is primarily achieved by disulfide bonds. Thus, the first turritoxins characterized are strikingly different from the conotoxins, suggesting divergent biochemical strategies in the venoms of different major groups included in the superfamily Conoidea.

Amino Acid Sequence↗
PubMed2005

Mass spectrometric and high performance liquid chromatography profiling of the venom of the Brazilian vermivorous mollusk Conus regius: feeding behavior and identification of one novel conotoxin.

Carnivorous mollusks belonging to the genus Conus paralyze their prey by injecting a rich mixture of biologically active peptides. Conus regius is a vermivorous member of this genus that inhabits Brazilian tropical waters. Inter-, intra-species and individual variations of cone snail venom have been previously reported. In order to investigate intra-specific differences in C. regius venom, its feeding behavior and the correlation between these two factors, animals were pooled according to gender, size and season of collection, and their venom composition was compared by high performance liquid chromatography (HPLC). Both the whole venom and one specific peak were monitored by HPLC. Chromatographic profiles revealed no significant differences in their peak areas, indicating that the venom composition, based solely in the presence or absence of the major peaks, is stable regardless of season, gender and size. Therefore, analysis of one given toxin, eluting in one of the major peaks, is representative among the population. Moreover, this work presents the identification of one novel conotoxin (rg11a), which amino acid sequence was deduced by mass spectrometry.

Amino Acid Sequence↗
PubMed1993

Toxityping rat brain calcium channels with omega-toxins from spider and cone snail venoms.

Different types of voltage-sensitive Ca2+ channels in the brain can be defined by specific ligands: L-type Ca2+ channels are uniquely sensitive to dihydropyridines, and N-type Ca2+ channels are selectively blocked by the Conus peptide omega-CTX-GVIA. Cloning data have revealed additional calcium channel types in mammalian brain for which selective ligands would be desirable. We describe binding experiments involving three newer ligands that block dihydropyridine- and omega-CTX-GVIA-resistant Ca channels: omega-Aga-IIIA and omega-Aga-IVA from venom of the spider Agelenopsis aperta and omega-CTX-MVIIC from Conus magus. [125I]omega-Aga-IVA binds with high affinity (IC50 = approximately 50 nM) to receptors in rat brain which may correspond to P-like calcium channels. A second high-affinity site (IC50 = approximately 1 nM) is defined by [125I]omega-CTX-MVIIC, proposed here to be on an "O"-type calcium channel. [125I]omega-Aga-IIIA targets homologous binding sites present on multiple Ca channel types. The IIIA sites overlap with the binding sites for [125I]omega-CTX-GVIA and [125I]omega-CTX-MVIIC. The IIIA sites do not overlap with the site defined by omega-Aga-IVA. Thus toxin ligands may be highly specific for a particular Ca channel (i.e., GVIA for the N-type channel) or exhibit broader specificity (i.e., omega-Aga-IIIA, which appears to bind L-, N-, P-, and O-type Ca2+ channels).

Agatoxins↗
PubMed2001

Cone venom--from accidental stings to deliberate injection.

Cone snails have long been of note due to their colorful shells and deadly venom. Over the years, a number of people who have encountered these molluscs have been injured or killed by their sting. Biochemical analysis of the venom components has revealed a plethora of peptides and proteins that target a variety of receptors and ion channels. Pharmaceutical companies are now utilizing the selectivity and potency of Conus-derived peptides to develop novel medications for pain, epilepsy and other disorders.

Animals↗
PubMed2005

Molecular interaction of delta-conotoxins with voltage-gated sodium channels.

Various neurotoxic peptides modulate voltage-gated sodium (Na(V)) channels and thereby affect cellular excitability. Delta-conotoxins from predatory cone snails slow down inactivation of Na(V) channels, but their interaction site and mechanism of channel modulation are unknown. Here, we show that delta-conotoxin SVIE from Conus striatus interacts with a conserved hydrophobic triad (YFV) in the domain-4 voltage sensor of Na(V) channels. This site overlaps with that of the scorpion alpha-toxin Lqh-2, but not with the alpha-like toxin Lqh-3 site. Delta-SVIE functionally competes with Lqh-2, but exhibits strong cooperativity with Lqh-3, presumably by synergistically trapping the voltage sensor in its "on" position.

Amino Acid Sequence↗
PubMed1996

Novel omega-conotoxins block dihydropyridine-insensitive high voltage-activated calcium channels in molluscan neurons.

We have identified two novel peptide toxins from molluscivorous Conus species that discriminate subtypes of high voltage-activated (HVA) calcium currents in molluscan neurons. The toxins were purified using assays on HVA calcium currents in the caudodorsal cells (CDCs) of the snail Lymnaea stagnalis. The CDC HVA current consists of a rapidly inactivating, transient current that is relatively insensitive to dihydropyridines (DHPs) and a slowly inactivating, DHP-sensitive L-current. The novel toxins, designated omega-conotoxins PnVIA and PnVIB, completely and selectively block the transient HVA current in CDCs with little (PnVIA) or no (PnVIB) effect on the sustained L-type current. The block is rapid and completely reversible. It is noteworthy that both PnVIA and PnVIB reveal very steep dose dependences of the block, which may imply cooperativity in toxin action. The amino acid sequences of PnVIA (GCLEVDYFCGIPFANNGLCCSGNCVFVCTPQ) and of PnVIB (DDDCEPPGNFCGMIKIGPPCCSGWCFFACA) show very little homology to previously described omega-conotoxins, although both toxins share the typical omega-conotoxin cysteine framework but have an unusual high content of hydrophobic residues and net negative charge. These novel omega-conotoxins will facilitate selective analysis of the functions of HVA calcium channels and may enable the rational design of drugs that are selective for relevant subtypes.

Amino Acid Sequence↗
PubMed2002

Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.

Mu-conotoxins are a family of peptides from the venoms of predatory cone snails. Previously characterized mu-conotoxins preferentially block skeletal muscle voltage-gated sodium channels. We report here the discovery (via cloning), synthesis, and electrophysiological characterization of a new peptide in this family, mu-conotoxin SmIIIA from Conus stercusmuscarum. Although mu-conotoxin SmIIIA shares several biochemical characteristics with other mu-conotoxins (the arrangement of cysteine residues and a conserved arginine believed to interact with residues near the channel pore), it has distinctive features such as the absence of hydroxyproline. In voltage-clamped dissociated neurons from frog sympathetic and dorsal root ganglia, the peptide inhibited the majority of tetrodotoxin-resistant sodium currents irreversibly; in contrast, tetrodotoxin-sensitive sodium currents were largely unaffected by the peptide. We believe that mu-conotoxin SmIIIA is the first specific antagonist of tetrodotoxin-resistant voltage-gated sodium channels to be discovered. Thus, the peptide provides a new and potentially useful tool to investigate the functional roles of tetrodotoxin-resistant voltage-gated sodium channels, including those that are found in sensory nerves that convey nociceptive information.

Amino Acid Sequence↗