Educational guide
Conotoxin - an overview
Chapters and Articles You might find these chapters and articles relevant to this topic. Introduction Conotoxins are members of a large family of highly potent peptide toxins (venoms), so named because they are released by the approximately 500 – 700 diverse s
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Chapters and Articles
You might find these chapters and articles relevant to this topic.
Introduction
Conotoxins are members of a large family of highly potent peptide toxins (venoms), so named because they are released by the approximately 500 – 700 diverse species of the predatory marine cone snail genus Conus (Fig. 1A) found in all tropical marine habitats (e.g., Becker and Terlau 2008; Cruz 1996; Glaser and Mayer 2009; Gray et al. 1988; Heading 2004; Tsetlin et al. 2009; Yoshiba 1984). The conotoxins rapidly and effectively paralyze the slow-moving cone snail's prey for easier predation. The majority of conotoxins are thought to produce this effect by an action on membrane voltage-gated or ligand-gated ion channels, but other targets include GPCRs (G protein-coupled receptors) and neurotransmitter transporters (e.g., Castellino and Prorok 2000; Ekberg et al. 2008; Favreau et al. 1999; Hamilton and Perez 1987; Lewis 2004). These and related actions generalize to mammalian voltage- and ligand-gated ion channels and other neurotransmitter-related processes and provide the basis for current pharmacotherapy and potential for new drug development (e.g., Armishaw and Alewood 2005; Glaser and Mayer 2009; Twede et al. 2009; Watters 2005).
Fig. 1. A: Conus textile. B: Conus geographus. C: Disulfide bonds form between Cys residues with m and n intermediate amino acids. D: α-Conotoxin from PnIB. E: ω-Conotoxin MVIIA (ziconotide). The disulfide bonds in D and E are indicated by arrows.
The mechanism of biological activity of conotoxins is highly dependent upon strict complementary structural determinants. Conotoxins are peptides (‘conopeptides’) commonly consisting of 10 – 30 amino acid residues (e.g., Craik and Adams 2007; Marx et al. 2006). However, they are not linear peptides; in addition to the usual thermodynamic impositions, typically one or more internal disulfide bonds impose folding constraints on their 3-dimensional structure (e.g., Bulaj and Olivera 2008; Walewska et al. 2008). ‘Conotoxin’ is the term commonly used when referring to disulfide-rich cone snail toxins; ‘conopeptide’ is a more general term used when referring to any peptide found in cone snail venom.
In a recent paper, Muttenthaler et al. (2010) report a facile method for synthesis and evaluation of conotoxin analogs that have diselenium bonds between selenocysteine rather than the native disulfide bonds between cysteine residues. These analogs adopt conformations similar to their disulfide counterparts and maintain, or in some cases exceed, their biological activity. As such, they offer promise as pharmacologic tools and also as possible therapeutic agents.
URL: https://www.sciencedirect.com/science/article/pii/S0024320510003188
Chapter
Introduction
The mu-conotoxins are a group of selective inhibitors of Na+ currents in skeletal muscle. Although related in action to tetrodotoxin (TTX) and Saxitoxin (STX) by their Na-channel blocking activity, the mu-conotoxins are structurally distinct and differ in channel selectivity. The first mu-conotoxin characterized was mu-conotoxin GIII A. It is a 22 amino acid long peptide derived from the cone snail, Conus geographus. Mu-conotoxin GIIIA is more specific for Na channel subtypes than either TTX or STX Cruz et al (1985). Mu-conotoxin GIIIA causes paralysis when injected into vertebrates. Mu-conotoxin binds to the same site on the skeletal muscle sodium channel Cestèle and Catterall (2000), however, in contrast to TTX and STX, mu-conotoxin GIIIA selectively targets only one TTX-sensitive voltage-gated sodium channel isoform, the skeletal muscle subtype, NaV1.4. Closely related peptides GIIIB and GIIIC have also been isolated from C. geographus. A fourth mu-conotoxin, PIIIA, from a different cone snail, C. purpurascens, also binds to the skeletal muscle sodium channel subtype, but can bind to and inhibit some other TTX-sensitive Na channels, although with decreased affinity Shon et al (1998), Safo et al (2000). The fifth mu-conotoxin is SmIIIA, from the venom duct of C. stercusmuscarumWest et al (2002).
URL: https://www.sciencedirect.com/science/article/pii/B9780080552323622214
1.08.7.2 The Conotoxins
The extremely complex libraries of short (usually 10–35 residue) peptide toxins elaborated by snails of the genus Conus have turned out to be a treasure trove of pharmacologically active materials, initially in the area of analgesia but now in inflammation and neurochemistry as well. In addition, separation of the individual peptides has led to fundamental biochemical studies in voltage-gated channels of all types. A recent paper by Olivera and collaborators (the person who has probably done more to realize the potential of these peptides than any other) should be consulted as a guide to the potential for these peptides in a variety of pharmacologic areas.208
Ziconotide (111; Figure 13) is a 25-residue peptide with three interlocking cystinyl bridges that was originally isolated by Olivera's group from Conus magus and was known as MVIIA toxin. It demonstrated a potent activity against voltage-gated Ca2+ channels, and because of its novel binding characteristics, Olivera coined the phrase ‘Janus ligand’ for this and other similar peptidic agents, as they appeared to have both a ‘docking face’ and a ‘locking face’ at the receptor level. The peptide demonstrated significant effects as an analgesic and was licensed to Neurex Inc., who then proceeded to synthesize over 200 variations on the structure, before eventually deciding that the original structure was optimal. Ziconotide was approved by the Food and Drug Administration (FDA) at the very end of 2004 for the treatment of intractable (phantom limb) pain under the trade name of Prialt.
Other conatoxins are in various stages of clinical or preclinical development. These include CGX-1007 (conantokin G) for neuropathic pain and intractable epilepsy, CGX-1160 (contulakin G from Conus geographus, a neurotensin agonist), R-conotoxin Vc1.1 from Conus victoriae for neuropathic pain, ω-conotoxin CVID from Conus catus for severe morphine-resistant pain, and χ-conotoxin MRIA/B for neuropathic pain.
URL: https://www.sciencedirect.com/science/article/pii/B008045044X000110
δ-Conotoxin SVIE
δ-Conotoxin SVIE (δ-CXTSVIE) is a conotoxin peptide delivered from the piscivorous cone snail, Conus striatus, which also uses the “harpoon” fish hunting method. It too is believed to act by increasing the excitability of the vertebrate neuromuscular junction by specific and high-affinity binding to voltage-sensitive Na+ channels. It was previously believed that these effects did not occur in mammalian skeletal muscle.129 However, these results have recently been challenged with the finding of potent long-lasting effects in rat skeletal muscle.124 Like δ-CXTPVIA, the time course of the neuromuscular effects of δ-CXTSVIE are unknown. However, what may give this neurotoxin a unique therapeutic action, is the finding that in vivo effects of δ-CXTPVIA on the neuromuscular junction can be reversed by washing preparations, whereas the effects of δ-CXTSVIE are more potent and persisted after washing for the entire testing period (45 min124). This suggests that intracellular changes are instigated by δ-CXTSVIE, which still persists after extracellular removal of the toxin. To our knowledge, no published study (in vitro or in vivo) has been conducted testing the effects of δ-CXTPVIA or δ-CXTSVIE on UA muscle activity.
URL: https://www.sciencedirect.com/science/article/pii/S1087079207000512
α-Conotoxins
Among the many components of cone snail (family: Conidae) venom are the α-conotoxins. α-Conotoxin IMI is a competitive antagonist of α7 at ∼100 nM, and of α9 at 10-fold higher concentrations. α-Conotoxin AuIB is fairly specific for α3-containing nAChRs, and also acts through a competitive mechanism. α-Conotoxin MII competitively blocks α6-containing nAchRs.
URL: https://www.sciencedirect.com/science/article/pii/B9780123742032002049
4.2.2 μ-Conotoxin PIIIA
μ-Conotoxins, derived from the venom of the Marine cone snail, are 14–26 polypeptides containing six cysteine residues [86]. μ-Conotoxins inhibit muscle and neuronal sodium ion channel currents by blocking ion channel pores [87]. Recently, it was shown that the skeletal muscle voltage-gated sodium channel NaV1.4 was blocked by three structurally distinct disulfide-bridge isomers of the μ-conotoxin PIIIA, known as μ-PIIIA-1, − 2, and − 3, with IC50 values of 46.7 nM, 103.2 nM, and 203.7 nM, respectively. The essential residue R14 of μ-PIIIA-1 binds substantially deeper in the pore than μ-PIIIA-2 and μ-PIIIA-3, according to molecular dynamic simulations, with the deeper insertion of the toxin playing important roles in high-affinity binding. The greater IC50 value of μ-PIIIA-1 relative to isomers 2 and 3 may be due to isomer-specific toxin directly blocking the NaV1.4 channel pore through allosteric modulation of the NaV1.4 channel gating [86].
URL: https://www.sciencedirect.com/science/article/pii/S0344033823006106
4.3.3 Knock-out of LBD by conotoxins
In this approach, we use agonist binding site specific conotoxin (CTx: from conus snails). For example, α-conotoxin MI (CTxMI) is used as a specific blocker for the αδ site. We incubated the HEK cells with CTxMI for 15 min before experiments. It renders the αδ site completely non-functional. It is used as an innovative strategy for KD, E1 and efficiency measurement of the individual agonist sites (Nayak, Vij, Bruhova, Shandilya, & Auerbach, 2019).
URL: https://www.sciencedirect.com/science/article/pii/S0091679X21001369
Venom
Each species has venom with 100 to 200 unique peptides, or conotoxins, that target voltage-gated and ligand-gated ion channels, as well as G protein–linked receptors.59 These small 12 to 30 amino acid peptide ligands have affinity for nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and N-methyl-d-aspartate receptors.60 C geographus mu-conotoxin, for instance, targets the ion-conducting pore of voltage-gated Na channels by physical occlusion.61 The venom paralyzes prey. One omega-conotoxin derivative, ziconotide, targets N-type calcium channels and has been approved by the FDA for intrathecal infusion for pain relief.62
URL: https://www.sciencedirect.com/science/article/pii/S0733862713000898
DESCRIPTION OF EVENT
Marine toxins are poisons of biologic origin that may be used as chemical weapons. These toxins are produced by a variety of organisms ranging from small microbes to fish and snails. These toxins are not infectious. Exposure to the toxins either by invenomation, ingestion, or inhalation may lead to a death through paralysis of cardiac or respiratory muscles.
Several marine toxins discussed here are further classified as neurotoxins. These toxins can interfere with the transmission of the nerve impulse by blocking specific ion channels. The neurotoxins vary in mechanism of action. The concentration of the exposure to the toxin is not indicative of its effects. Several toxins can cause seizures or paralysis in nanomolar concentrations, others may cause gastrointestinal upset or blindness in much larger concentrations.
Three of the marine toxins classified as neurotoxins are saxitoxin, conotoxin, and tetrodotoxin. The fourth toxin—palytoxin—exerts its effects on all cell membranes and is not classified as a neurotoxin.
URL: https://www.sciencedirect.com/science/article/pii/B9780323032537501412
2024, Biomedicine & PharmacotherapyJorge L. Díaz-GómezIrene Martín-EstalElizabeth Rivera-AboytesRamón Alonso Gaxiola-MuñízCésar A. Puente-GarzaSilverio García-LaraFabiola Castorena-Torres
5.4.2 Motor activity regulation
Parkinson’s disease, schizophrenia, and addictive processes of drug abuse are disorders of the central and peripheral nervous systems. In these diseases, neuronal nicotinic acetylcholine receptors (nAChRs) play pivotal roles in regulating transmitter release, cell excitability, neuronal integration, and motor regulation (Table 2).
The dysfunction of nAChRs has been implicated in various severe pathologies. Conotoxins, are potent antagonists of various nAChR subtypes and participate in prey capture through muscle paralysis. Peptides such as RegIIA [89], CIA and CIB [22], δ-conotoxins [84], 3/5 α-conotoxin MilIA [90], RgIA-5474 [91], Czon1107, CIA and CIB [22], and heterologous hα3β4 [92] have exhibited effective activity. Another group includes snake venom α-neurotoxin peptides derived from the Ly6 family (Ly6/uPAR protein, SLURP1, and membrane-attached Ly-6/neurotoxin, Lynx1) that act as myorelaxants and analgesics [93]. Additionally, azemiopsin, a linear peptide from viper venom, is an effective local muscle relaxant [5,94].
A novel synthetic heat-resistant peptide derived from scorpion venom (SVHRSP) has been reported to exert protective effects against attenuated dopaminergic neurodegeneration and motor dysfunction [95]. MT9, a natural peptide derived from mamba venom, antagonizes the muscarinic type 2 receptor and reverses M2R-agonist-induced relaxation in human arteries [96].
Mechanisms of action other than nAChRs involve voltage-gated ion channels, which are critical for controlling the function of excitable cells. Human genetic studies have shown that the aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain [97]. The effects of peptide toxins have shed light on the structure–function relationships of these channels. For example, increased T-type calcium currents are found in various pathological conditions owing to the upregulation of specific CaV3 subtypes. Tarantula venom ω-Avsp1a inhibited specific T-type CaV channel subtypes [77].
Similarly, conanokines function as allosteric antagonists of N-methyl-D-aspartate receptor ion channels. These receptors have considerable functional plasticity depending on their subunit combination, which are regionally and developmentally controlled in the brain [98]. In the search for subtype-selective blockers of CaV channels, the peptide ω-TRTX-Cc1a from tarantula venom was effective as an inhibitor of CaV2.3 channels [16].
Functional NaV channels are involved in regulating microglial function and inflammation associated with the pathology of Parkinson’s disease. Here, SVHRSP inhibited neuroinflammation and protected dopaminergic neurons by downregulating microglial cells [99,100].
URL: https://www.sciencedirect.com/science/article/pii/S0753332223018139