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CONOTOXINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Conotoxins are neurotoxic peptides that are produced by various cone snails (Conus species) (Olivera et al, 1985). There are more than 500 species distributed throughout the tropical Pacific and Indian Oceans (Annadurai et al, 2007).

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Cone snail toxins
    2) Conopeptides
    3) Conus toxins
    4) alpha-conotoxins
    5) Conopressin
    6) Convulsant
    7) Geographutoxin
    8) GI
    9) GIII
    10) GIIIA
    11) GIV
    12) iota-conotoxins
    13) K-conotoxins
    14) "King Kong Peptide"
    15) MAC
    16) MI
    17) mu-conotoxins
    18) omega-conotoxins
    19) SI
    20) "Sleeper"
    21) Toxin III
    22) TxIA
    23) TxIIa
    24) TxIB ("King Kong Peptide")
    25) Virgotoxin
    RELATED COMPOUNDS - WHOLE UNPURIFIED VENOMS
    1) Conus magus venom
    2) Conus striatus venom
    3) References: (Olivera et al, 1988; Spira et al, 1993; Stiles, 1993)

Available Forms Sources

    A) SOURCES
    1) Conotoxins are found in the venom of cone snails. Conus species are found throughout the world, but the species which are known to cause fatal envenomations in man have been primarily in the Indo-Pacific area and generally prey on fish (Olivera et al, 1988) Baldomero et al, 1988).
    a) Cone snails are divided into 3 groups, based on their prey:
    1) Vermivorous (worm hunting; the largest group)
    2) Molluscivorous (snail hunting)
    3) Piscivorous (fish hunting)
    b) The venom of Piscivorous cone snails make use of 'toxin cabals,' a group of conopeptides that act in a coordinated manner to achieve a desired physiologic effect. A "lightening strike" toxin cabal inhibits voltage-gated sodium channels and blocks potassium channels, resulting in immediate immobilization. A second 'motor cabal' acts at neuromuscular junctions by inhibiting presynaptic calcium channels and sodium involved in the muscle action potential (Norton & Olivera, 2006).
    2) The Conus geographus have been most widely associated with human fatalities; other fish-eating cone snails which are potential human hazards are C. tulipa, C. magus, C. purpurascens and 6 other species (Olivera et al, 1988). Other species have the potential for causing significant human injury.
    B) USES
    1) Because of their interesting pharmacology and specificity, various conotoxins are used in biochemical investigations (Vanguelin et al, 1991).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Conotoxins are neurotoxins derived from marine cone snails of the genus Conus. The conotoxins are in the toxin sacs of these predatory snails. Because of their interesting pharmacology and specificity, various conotoxins are used in biochemical investigations.
    B) TOXICOLOGY: Conotoxins are made up of 12 to 40 amino acid residues. There are probably over 50,000 different conotoxins in existence from perhaps 500 different species of cone snails. Conotoxins have a variety of mechanisms of action, most of which have not been determined.
    1) However, it appears that many of these peptides modulate the activity of ion channels, the most common types of conotoxins and their effects are as follows:
    a) Alpha-conotoxins are antagonists of nicotinic acetylcholine receptors, including the neuromuscular junction.
    b) Mu-conotoxins are voltage-gated sodium channels antagonists.
    c) G-conotoxins can slow voltage gated sodium channel inactivation and prolong the action potential in neurons.
    d) Omega-conotoxins can hinder the voltage-dependent entry of calcium into the nerve terminal and inhibit acetylcholine release.
    e) Kappa-conotoxins are voltage-gated potassium channels antagonists.
    f) Conantonkins are NMDA glutamate receptor antagonists.
    C) EPIDEMIOLOGY: Conus species are found throughout the world, but the species which are known to cause fatal envenomations in man have been primarily in the Indian-Pacific oceans, especially off the coast of Australia. Cone snails do not occur naturally off the coast of the United States (Hawaii an exception) or Europe. Most human deaths have occurred when divers and fishermen have accidentally stepped on a cone snail, or in the process of harvesting the snails. About 30 deaths have been documented, but there are probably many more deaths that have not been reported. A high risk of death is associated with envenomation by certain species of cone snails, particularly C. geographus, C textile, and C. marmoreus.
    D) WITH POISONING/EXPOSURE
    1) LOCAL EFFECTS: Initial signs and symptoms may be local ischemia, stinging, numbness, or burning at the puncture site and some cyanosis.
    2) SYSTEMIC EFFECTS: The venom is predominantly neurotoxic. Numbness and tingling may spread rapidly to involve the entire body. The lips and mouth are particularly affected. In a moderate envenomation, general muscle weakness, ataxia, diminished reflexes, slurred speech, and difficulty swallowing and breathing may develop. In severe cases, effects may progress to the inability to speak, diplopia, unconsciousness, paralysis of voluntary muscles, and respiratory failure. Deaths have been reported.

Laboratory Monitoring

    A) No routine laboratory tests are required unless otherwise clinically indicated.
    B) Monitor pulse oximetry and/or arterial blood gases in patients with significant weakness and dyspnea. Negative inspiratory force may be used to predict the need for intubation in patients with weakness.
    C) In acutely ill individuals, obtain a complete blood count, electrolytes, and coagulation studies.
    D) Assays for conotoxins are not used in the clinical management of patients.

Treatment Overview

    0.4.7) BITES/STINGS
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Cleanse the wound and immobilize the affected area. Give tetanus toxoid if immunization is not current. Give appropriate analgesia. Immersing the affected area in hot water (110 to 115 degrees F) for one-half to one hour many result in pain relief, but this treatment is not consistently effective. Keep the stung extremity in a dependent position, and keep the patient still. Tourniquet use is not recommended, because it may result in significant iatrogenic injury. No role exists for attempting to suction conotoxins from a wound.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Cardiovascular and respiratory support are the primary role of clinical management. Ensure that an adequate airway and breathing are maintained. Patients may develop oropharyngeal muscle paralysis, and the risk of aspirating vomitus is possible. Assess circulation and give fluids and pressors, if necessary.
    C) DECONTAMINATION
    1) There is NO role for decontamination.
    D) AIRWAY MANAGEMENT
    1) Perform early intubation for a patient with dyspnea or signs of muscular weakness.
    E) ANTIDOTE
    1) No antivenom is available.
    F) ENHANCED ELIMINATION
    1) There is no role for enhanced elimination.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: There are no recommendations as to when to send an adult or child to a healthcare facility after exposure. Patients that develop symptoms should seek medical care.
    2) OBSERVATION CRITERIA: Mild envenomations, with no systemic effects, should resolve within 6 to 8 hours. If no further symptoms develop, the patient may be discharged to home.
    3) ADMISSION CRITERIA: Any patient showing systemic manifestations should be admitted to an intensive care for monitoring.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison control center for patients with more than mild local symptoms.
    H) DIFFERENTIAL DIAGNOSIS
    1) Anaphylaxis; coelenterate and jellyfish envenomations; sea snake envenomation; ciguatera and shellfish toxicity; lionfish envenomations; octopus envenomations, submersion injury, or decompression sickness.

Range Of Toxicity

    A) TOXICITY: The amount of venom which is injected during a sting varies considerably. The strength and site of action of the venom also varies by the species involved. A single sting is potentially lethal.

Clinical Effects

Summary Of Exposure

    A) USES: Conotoxins are neurotoxins derived from marine cone snails of the genus Conus. The conotoxins are in the toxin sacs of these predatory snails. Because of their interesting pharmacology and specificity, various conotoxins are used in biochemical investigations.
    B) TOXICOLOGY: Conotoxins are made up of 12 to 40 amino acid residues. There are probably over 50,000 different conotoxins in existence from perhaps 500 different species of cone snails. Conotoxins have a variety of mechanisms of action, most of which have not been determined.
    1) However, it appears that many of these peptides modulate the activity of ion channels, the most common types of conotoxins and their effects are as follows:
    a) Alpha-conotoxins are antagonists of nicotinic acetylcholine receptors, including the neuromuscular junction.
    b) Mu-conotoxins are voltage-gated sodium channels antagonists.
    c) G-conotoxins can slow voltage gated sodium channel inactivation and prolong the action potential in neurons.
    d) Omega-conotoxins can hinder the voltage-dependent entry of calcium into the nerve terminal and inhibit acetylcholine release.
    e) Kappa-conotoxins are voltage-gated potassium channels antagonists.
    f) Conantonkins are NMDA glutamate receptor antagonists.
    C) EPIDEMIOLOGY: Conus species are found throughout the world, but the species which are known to cause fatal envenomations in man have been primarily in the Indian-Pacific oceans, especially off the coast of Australia. Cone snails do not occur naturally off the coast of the United States (Hawaii an exception) or Europe. Most human deaths have occurred when divers and fishermen have accidentally stepped on a cone snail, or in the process of harvesting the snails. About 30 deaths have been documented, but there are probably many more deaths that have not been reported. A high risk of death is associated with envenomation by certain species of cone snails, particularly C. geographus, C textile, and C. marmoreus.
    D) WITH POISONING/EXPOSURE
    1) LOCAL EFFECTS: Initial signs and symptoms may be local ischemia, stinging, numbness, or burning at the puncture site and some cyanosis.
    2) SYSTEMIC EFFECTS: The venom is predominantly neurotoxic. Numbness and tingling may spread rapidly to involve the entire body. The lips and mouth are particularly affected. In a moderate envenomation, general muscle weakness, ataxia, diminished reflexes, slurred speech, and difficulty swallowing and breathing may develop. In severe cases, effects may progress to the inability to speak, diplopia, unconsciousness, paralysis of voluntary muscles, and respiratory failure. Deaths have been reported.

Heent

    3.4.2) HEAD
    A) Numbness and tingling of the lips, mouth, and throat can occur (Cruz & White, 1995; Ellis, 1975).
    3.4.3) EYES
    A) BLURRED VISION may be present (Cruz & White, 1995; Halstead, 1978).
    B) DIPLOPIA may be present (Cruz & White, 1995; Halstead, 1978).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Weak and rapid pulse has occurred in moderate to severe cases (Buckley & Porges, 1956; Kohn, 1958).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea has been reported, but respiratory depression is usually absent (Halstead, 1980; Buckley & Porges, 1956).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Respiratory failure is a rare complication of severe envenomation and is the likely cause of death in fatalities (Cruz & White, 1995).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PARALYSIS
    a) Death in experimental animals due to alpha conotoxins is due to respiratory muscle paralysis (Marshall & Harvey, 1990).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) CONUS OMARIA: Envenomation in an 8-year-old girl caused slurred speech, shallow breathing, depressed deep tendon reflexes, and tachycardia within 2 hours. This progressed to respiratory paralysis and coma. With respiratory support she awoke after 2 hours and recovered completely after 20 hours (Cruz & White, 1995).
    B) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) Paralysis may develop in severe cases (Cruz & White, 1995; Flecker, 1936).
    C) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Numbness and tingling may start at the puncture site and spread to the entire body (Cruz & White, 1995; Ellis, 1975).
    b) Conus bayani toxin has been tested in animals as a local anesthetic (Kasinathan et al, 1991).
    D) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) Incoordination and ataxia may occur in less severe envenomations (Cruz & White, 1995; Buckley & Porges, 1956).
    E) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Mental confusion has been reported in Conus envenomations (Buckley & Porges, 1956).
    F) DISTURBANCE IN SPEECH
    1) WITH POISONING/EXPOSURE
    a) Slurred speech may develop (Cruz & White, 1995).
    b) Aphonia may be present (Halstead, 1978).
    G) ABNORMAL VISION
    1) WITH POISONING/EXPOSURE
    a) Diplopia and blurred vision have been described after Conus geographus envenomation (Cruz & White, 1995).
    H) ABNORMAL REFLEX
    1) WITH POISONING/EXPOSURE
    a) Deep tendon reflexes may be depressed (Cruz & White, 1995).
    I) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) Generalized weakness develops in moderate envenomations; it may progress to respiratory failure in severe envenomations (Cruz & White, 1995).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DYSPHAGIA
    1) WITH POISONING/EXPOSURE
    a) Dysphagia has been reported in cases of human envenomation (Cruz & White, 1995; Buckley & Porges, 1956).
    B) NAUSEA
    1) WITH POISONING/EXPOSURE
    a) Nausea may be present after a cone shell sting, but significant gastrointestinal or genitourinary symptoms are usually absent (Halstead, 1978).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PERIPHERAL ISCHEMIA
    1) WITH POISONING/EXPOSURE
    a) Local ischemia, swelling, and numbness may occur around the puncture wound (Buckley & Porges, 1956).
    b) A localized reaction may remain for several weeks (Halstead, 1980; Kizer, 1990).
    B) PAIN
    1) WITH POISONING/EXPOSURE
    a) A burning or stinging sensation at the envenomation site is a common initial symptom (Veraldi et al, 2011; Cruz & White, 1995; Halstead, 1980).
    C) ITCHING OF SKIN
    1) WITH POISONING/EXPOSURE
    a) General pruritus is a complaint of some victims (Halstead, 1978).
    D) ABSCESS
    1) WITH POISONING/EXPOSURE
    a) CONUS TEXTILE: CASE REPORT: A 31-year-old man presented with a right buttock abscess 2 weeks after placing a shell species of Conus textile Linnaeus 1758 in his swimming trunks while snorkeling in the south-west Pacific Ocean. He reported a burning sensation to the right buttock minutes after collecting the shell, painful swelling 3 hours after, and a fever of less than 38 degrees C accompanied by general malaise 2 days after the event. At presentation his temperature was 37.8 degrees C, the abscess was red, 3.5 cm in diameter, and surrounded by hard, erythematous edema with pus draining from 2 fistulas. Laboratory analysis showed leukocytosis, increased erythrocyte sedimentation rate, and increased C-reactive protein. Abscess cultures were positive for Escherichia coli, Staphylococcus aureus, and Peptostreptococcus sp. He was treated with wound care using sodium hypochlorite packing, oral amoxicillin/clavulanic acid, oral metronidazole, and analgesics. He recovered fully within 6 weeks (Veraldi et al, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No routine laboratory tests are required unless otherwise clinically indicated.
    B) Monitor pulse oximetry and/or arterial blood gases in patients with significant weakness and dyspnea. Negative inspiratory force may be used to predict the need for intubation in patients with weakness.
    C) In acutely ill individuals, obtain a complete blood count, electrolytes, and coagulation studies.
    D) Assays for conotoxins are not used in the clinical management of patients.

Methods

    A) BIOASSAYS
    1) Bioassays are available for determining relative venom toxicities of various Conus species (Fainzilber et al, 1991; Fainzilber & Zlotkin, 1992; Spira et al, 1993).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.6) DISPOSITION/BITE-STING EXPOSURE
    6.3.6.1) ADMISSION CRITERIA/BITE-STING
    A) Any patient showing systemic manifestations should be admitted to an intensive care for monitoring.
    6.3.6.2) HOME CRITERIA/BITE-STING
    A) There are no recommendations as to when to send an adult or child to a healthcare facility after exposure. Patients that develop symptoms should seek medical care.
    6.3.6.3) CONSULT CRITERIA/BITE-STING
    A) Consult a medical toxicologist or poison control center for patients with more than mild local symptoms.
    6.3.6.5) OBSERVATION CRITERIA/BITE-STING
    A) Mild envenomations, with no systemic effects, should resolve within 6 to 8 hours. If no further symptoms develop, the patient may be discharged to home.

Monitoring

    A) No routine laboratory tests are required unless otherwise clinically indicated.
    B) Monitor pulse oximetry and/or arterial blood gases in patients with significant weakness and dyspnea. Negative inspiratory force may be used to predict the need for intubation in patients with weakness.
    C) In acutely ill individuals, obtain a complete blood count, electrolytes, and coagulation studies.
    D) Assays for conotoxins are not used in the clinical management of patients.

Abstracts

Case Reports

    A) ADULT
    1) ROUTE OF EXPOSURE
    a) STING: Most Conus stings occur when humans step on or near a Conus shell or pick one up to collect the shell.
    1) There is usually immediate stinging, burning, and numbness in the affected area. This sensation may spread to the entire body, and particularly the mouth and lips. In moderate to severe cases, muscle incoordination, dysphagia, and paralysis may ensue.
    2) Symptoms usually increase in severity for 3 to 6 hours and then decrease during the next 24 hours. A localized reaction may persist for several weeks.

Range Of Toxicity

Summary

    A) TOXICITY: The amount of venom which is injected during a sting varies considerably. The strength and site of action of the venom also varies by the species involved. A single sting is potentially lethal.

Minimum Lethal Exposure

    A) SUMMARY
    1) The venoms of fish-hunting cone snails (especially C. geographus; also C. tulipa, C. magus, C. purpurascens and 6 other species) are principally of potential danger to humans; venoms of other cone snails are chiefly dangerous to invertebrates (Olivera et al, 1988).
    2) A single sting is potentially lethal (Halstead, 1978; Olivera et al, 1988).
    3) Although these snails generally hunt fish, other mollusks, or worms, a 3 to 5 inch C. geographus can kill a man, and about 20 fatalities have been reported due to accidental stings. Many human fatalities have been due to the C. geographus (Olivera et al, 1988).
    4) Conus envenomations or stings are of the puncture wound variety and have occurred when the cone shell was disturbed or the snail was handled outside of its shell (Olivera et al, 1985; Olivera et al, 1988). Ejection of the venom from the proboscis has been observed (Olivera et al, 1988) and thus may be another means of potential exposure.
    B) ANIMAL DATA
    1) Doses of 20 to 80 mcg/kg produced neuromuscular blockage in cats (Marshall & Harvey, 1990).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) No toxic blood or serum concentration has been established.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 12 mcg/kg (Cruz et al, 1978)

Pharmacology Toxicology

Toxicologic Mechanism

    A) The toxicity of conotoxins vary and are specific for vertebrates, invertebrates or worm-hunting species (vermivorous), depending on the feeding preference of the Conus species and their defense needs (Spira et al, 1993; Olivera et al, 1988). The evolution of conotoxin expression patterns is dynamic, and multiple conotoxin molecules may be required to block particular receptor targets (Duda & Remigio, 2008).
    1) The venoms of piscivorous Conus species (fish eaters) have a 10 to 30 times greater effect in vertebrates than in invertebrates, most likely secondary to the similarity between fish and mammalian nicotinic receptors. The venoms of five vermivorous species had no effect on mollusks or vertebrates, but were toxic to annelids (Fainzilber et al, 1991). TxIA, TxIIA and TxIB have paralytic activity in molluscs but not in arthropods or vertebrates (Spira et al, 1993).
    B) Fish-hunting Conus species have toxins (e.g., omega conotoxins) in their venoms which cause paralysis by presynaptically or postsynaptically blocking neuromuscular synapses via effects on voltage-sensitive calcium channels. The Conus geographus also has toxins which inhibit electrical neuromuscular transmission and toxins similar to alpha bungarotoxin and tetrodotoxin (Olivera et al, 1988).
    C) Alpha conotoxins, GI, MI and SI are postsynaptic neurotoxins which inhibit the nicotinic acetylcholine receptor and bind to similar sites on this receptor as alpha bungarotoxin, curare or cobra venom toxins (Olivera & Cruz, 2001; Olivera et al, 1988; Stiles, 1993). Alpha conotoxins cause death by paralysis of the respiratory muscles (Marshall & Harvey, 1990).
    1) Alpha conotoxin effects were reversed by neostigmine (Marshall & Harvey, 1990; McManus & Musick, 1985) Hasimoto et al, 1985).
    2) Alpha-IMI, alpha-IMII, and alpha-RgIA are alpha4/3 toxins which inhibit nicotinic acetylcholine receptors (Ellison & Olivera, 2007).
    D) GIIIA, GIIIB, GIIIC, toxin III, and geographutoxin are Mu conotoxins. Mu conotoxins block propagation of action potentials in vertebrate muscle membranes by inhibiting voltage-sensitive sodium channels; the binding sites are similar to the binding sites for tetrodotoxin and saxitoxin (Olivera & Cruz, 2001; Olivera et al, 1988; Olivera et al, 1985). GIIIA binds to muscle sodium channels but does not competitively inhibit the binding of cobra and alpha bungarotoxins to the acetylcholine receptor (Stiles, 1993).
    E) Omega conotoxins inhibit neuronal calcium channels (Olivera & Cruz, 2001; Olivera et al, 1988). Omega toxins differ greatly in their effects on various species (Olivera et al, 1985).
    F) Virgotoxin, a cardiotonic protein obtained from Conus virgo, has a direct action on vertebrate cardiac muscle. This action can be abolished with verapamil (Shanmuganandam et al, 1991).
    G) Conotoxin GIV (from C geographus) and MAC (from C magus) are larger polypeptides which have excitatory effects (Olivera et al, 1988).
    H) The effects of unpurified venoms of Conus species have been reviewed by Olivera et al (1988). Unpurified venom of C. magus can induce spontaneous contractions in skeletal muscle, possibly by increasing inward sodium currents. The venom of C. striatus increases excitability of neurons and skeletal muscle and may block potassium channels (Olivera et al, 1988).
    1) Conus striatus venom increases the likelihood of spontaneous and repetitive firing of action potentials based on studies in myelinated nerves. The venom caused sodium channels to open at potentials below the typical resting potential, opened sodium channels at voltages in which the channels are usually closed, stabilizes the open state of the sodium channel, and slowed both inactivation and deactivation of the sodium channels (Hahin et al, 1991).
    2) Serotonin has been identified in the venom of Conus imperialis (McIntosh et al, 1993).
    I) Conotoxins affect different physiologic targets. Below is a partial list of the toxins (some duplicates due to non-standardized nomenclature) and their known or proposed targets (Olivera & Cruz, 2001; Olivera et al, 1985; Olivera et al, 1988; Oyama et al, 1987; Myers et al, 1990; Speroni et al, 1991; Stiles, 1993; Utkin et al, 1994; Ellison & Olivera, 2007; Ellison et al, 2008; Fiedler et al, 2008):
    1) Table 1
     ToxinTarget
    1.Alpha-conotoxinAcetylcholine receptor
    2.ConopressinPossibly smooth muscle
    3.ConvulsantUnknown
    4.ConantokinsNMDA receptors
    5.GI (alpha)Acetylcholine receptor
    6.GIIIAMuscle sodium channels
    7.i-conotoxinsVoltage-gated sodium channels
    8.K-conotoxinsPotassium channels
    9.MIAcetylcholine receptor
    10.Mu-conotoxinsMuscle sodium channels
    11.Omega-conotoxinsVoltage-sensitive presynaptic calcium channels (blocks acetylcholine release)
    12.SIAcetylcholine receptor
    13.Sigma5-HT3 receptor

References

General Bibliography

    1) Annadurai D, Kasinathan R, & Lyla PS: Acute toxicity effect of the venom of the marine snail, Conus zeylanicus. J Environ Biol 2007; 28(4):825-828.
    2) Buckley EE & Porges N: Venoms. Pub Number 44, American Association For the Advancement of Science, Washington, DC, 1956.
    3) Burnett JW, Calton GJ, & Morgan RT: Cone snails. Cutis 1987; 39:109.
    4) Cruz LJ & White J: Clinical toxicology of Conus snail stings in Handbook of Clinical Toxicology of Animal Venoms and Poisons, Meier J & White J (eds), CRC Press, New York, NY, 1995.
    5) Cruz LJ, Gray WR, & Yosh Kami D: Conus venoms: a rich source of neuroactive peptides. J Toxicol Toxin Reviews 1985; 4:107-132.
    6) Cruz LZ, Gray WR, & Olivera BM: Purification and properties of myotoxin from Conus geographus. Arch Biochem Biophys 1978; 190:539-548.
    7) Duda TF & Remigio EA: Variation and evolution of toxin gene expression patterns of six closely related venomous marine snails. Mol Ecol 2008; 17(12):3018-3032.
    8) Ellis MD: Dangerous Plants, Snakes, Arthropods and Marine Life-toxicity and Treatment, Drug Intelligence Publications, Inc, Hamilton, IL, 1975.
    9) Ellison M & Olivera BM: Alpha4/3 conotoxins: phylogenetic distribution, functional properties, and structure-function insights. Chem Rec 2007; 7(6):341-353.
    10) Ellison M, Feng ZP, Park AJ, et al: Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J Mol Biol 2008; 377(4):1216-1227.
    11) Fainzilber M & Zlotkin E: A new bioassay reveals mollusc-specific toxicity in molluscivorous conus venoms. Toxicon 1992; 30:465-469.
    12) Fainzilber M, Gordon D, & Zlotkin E: Intervertebrate specific neurotoxins from nonpiscivorous Conus venoms, 10th World Congress on Animal, Plant, and Microbial Toxins, Singapore, China, 1991.
    13) Fiedler B, Zhang MM, Buczek O, et al: Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels Na(V)1.2, 1.6 and 1.7. Biochem Pharmacol 2008; 75(12):2334-2344.
    14) Flecker H: Cone shell mollusc poisoning, with report of a fatal case. Med J Aust 1936; 464-466.
    15) Hahin R, Wang G, & Shapiro BI: Alterations in sodium channel gating produced by the venom of the marine mollusc Conus striatus. Toxicon 1991; 29:245-259.
    16) Halstead BW: Dangerous Marine Animals That Bite, Sting, Shock, Are Non-edible (2nd Ed), Cornell Maritime Press, Centerville, MD, 1980.
    17) Halstead BW: Poisonous and Venomous Marine Animals of the World (Rev. Ed), The Darwin Press Inc, Princeton, NJ, 1978.
    18) Kasinathan R, Ramu YD, & Ravichandran V: Pharmacological studies on Conus bayani from southeast coast of India, 10th World Congress on Animal, Plant, and Microbial Toxins, Singapore, China, 1991.
    19) Kizer KW: When a stingray strikes. Treating common marine envenomations. Physician Sports Med 1990; 18:92-109.
    20) Kohn AJ: Recent cases of human injury due to venomous marine snails of the genus Conus. Hawaii Med J 1958; 17:528-532.
    21) Marshall IG & Harvey AL: Selective neuromuscular blocking properties of alpha-conotoxins in vivo. Toxicon 1990; 28:231-234.
    22) McIntosh JM, Foderaro TA, & Li W: Presence of serotonin in the venom of Conus imperialis. Toxicon 1993; 31:1561-1566.
    23) McManus OB & Musick JR: Postsynaptic block of frog neuromuscular transmission by conotoxin GI. J Neuroscience 1985; 5:110-116.
    24) Middlebrook JL: Production and characterization of monoclonal antibodies to conotoxin G1, 10th World Congress on Animal, Plant, and Microbial Toxins, Singapore, China, 1991.
    25) Myers RA, McIntosh JM, & Imperial J: Peptides from Conus venoms which affect Ca++ entry into neurons. J Toxicol Toxin Rev 1990; 9:179-202.
    26) Norton RS & Olivera BM: Conotoxins down under. Toxicon 2006; 48(7):780-798.
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