Conidae
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The dramatic increase in sport diving, ecotourism, and island and coastline travel, perhaps inevitably, has returned people to the sea. Curiosity about our chondrichthyan ancestors, as well as a desire to explore that 70% of our biosphere that remains largely enigmatic, has fostered a siren call to exotic realms. Dangers exist in the sea, as with any environment for which humans are poorly adapted. Contact with hazardous marine organisms is not the least of these dangers.
Many sea creatures have improved their survival through the evolutionary development of offensive and defensive systems that are often elaborate mechanisms for delivering poison or venom to prey or predator. Most of these organisms live in temperate to tropical oceans, especially in the Indo-Pacific regions. Vast arrays of vertebrate and invertebrate creatures can envenomate humans. This article focuses on the more than 600 members of the invertebrate Conidae family of the phylum Mollusca and the class Gastropoda (ie, the cone shells or snails). See the image below.
In the last four decades, toxinologists around the world have elucidated a wealth of information on the various classes of constituent proteins and peptides that provide each cone with its own distinctive, complex, and sophisticated bioarmamentarium. More than 2,000 toxins from an estimated more than 70,000 bioactive peptides have been identified in the Conus genus. [1] These venoms serve the cone as a primary weapon to capture prey, as defense, and possibly for other functions. [2, 3]
See Deadly Sea Envenomations, a Critical Images slideshow, to help make an accurate diagnosis.
Cone shells are carnivorous; they are divided into three groups, according to their prey items: molluscivorous (hunt other gastropods; 25% genus), vermivorous (hunters of polychaete and other worms), or piscivorous (fish hunting; 10% genus). The largest group of cones are vermivores, encompassing 65% of the genus. Their habitats extend from shallow, intertidal areas to extreme deepwater areas. These marine organisms inhabit primarily tropical marine environments in the Western Atlantic, Indian, and Pacific oceans; however, a few species are found in cooler environments. Cone shells are predominantly nocturnal, burrowing in the sand and coral during the daytime.
Like all gastropods, cone snails propel themselves along the ocean floor or reefs by their muscular foot. The foot muscle, or columellar, also contracts to pull the foot in and close the aperture of the shell. To capture a much faster prey in a highly dynamic marine environment, this relatively slow-moving snail has evolved into one of the fastest known predators in the animal kingdom, with the average attack lasting only milliseconds. In an attack, the cone shells inject a cocktail of small, rapidly acting, disorienting, paralytic, and lethal oligopeptide toxins, each 15-30 residues long, into the prey.
Almost 70,000 different conotoxin peptides have been identified to date in different groups of cones. These potent peptides, which fold into small highly structured frameworks, largely target ion channels, either voltage- or ligand-gated receptors and transporters in excitable cells. Conantakin G, exclusive to piscivore cones, subdues prey by targeting the NMDA receptor, causing sleep. [4] In the Gastridium clade of fish-hunting cones, including Conus geographus and Conus tulepa, fish insulinlike growth factors are highly expressed in the distal duct segment. These may act in prey to activate insulin receptors, mimicking the effects of insulin and causing prey “insulin shock” with disorientation. [5, 6] Venom mixtures are specific to each cone shell species, containing 30-200 conotoxin peptides and proteinaceous materials including proteases and phospholipids. Cones are able to deploy different venom mixtures for prey capture and defense. [7] A group of conopeptides, described as a cabal, act in a coordinated manner to produce a specific physiologic endpoint such as inhibition of voltage-gated sodium channel activation, calcium channel activation, and potassium channel block, resulting in massive depolarization of axons at the injection site, or activate insulin receptors, causing disorientation and complete block of nerve action potential propagation in the prey and its immediate immobilization. Different toxic cabals in the same venom may act on the same class of target via different mechanisms. Numerous disulfide bonds determine a specific small spatial shape for each toxin to better fit the target. These disulfide bonds also confer stability to the toxins, one result of which is their inability to be easily broken down by heat treatment. [8]
The first case of human envenomation by a cone shell was cited in 1706. Thirty-one cases of human envenomation, with occasional fatalities, have been documented worldwide. Human envenomations have involved 18 species of cone shells, most involving piscivores, including C geographus (responsible for approximately 85% of all lethal cases reported), Conus catus, Conus aulicus, Conus gloria-maris, Conus omaria, Conus magus, Conus striatus, Conus tulipa, and Conus textile.
Snail shell anatomy can be divided into two main portions: the body whorl and the spire. The body whorl, the lower portion of the shell, contains the soft snail body. The spire, or pointed top of the shell, can be different shapes. The whorl contains the portions of the snail essential for prey capture and movement. The cone shell detects its prey via the siphon, which is covered with chemoreceptors, although limited visual signaling may also be involved. The false mouth can be extended to engulf its prey, with a muscle contracted to retract the mouth back into the shell.
Venom, with different conotoxins formed rapidly in various portions of the venom duct due to different conotoxin gene expression profiles, [9, 10] is stored in a less toxic milky slurry in the venom bulb. When required, the precursor undergoes enzymatic cleavage of the signal peptide and the propeptide forms appropriate disulfide linkages. [11] The mature toxic solution is then delivered via a detachable radula. The radula is a dartlike, hollow, chitinous barb, formed in the radular sheath and delivered, after receiving venom in the buccal cavity, by a long, extensible proboscis. The venom sac contains approximately 20 radulae. The muscular proboscis, which may extend more than the full length to the shell spire in some species, touches a prey item and then thrusts one radula (or more, in some piscivorous cones) into the prey via circular muscles at its anterior tip. Approximately 1 to 50 microliters of venom are delivered by a radula. Venom rapidly diffuses through the poisoned prey. The radula remains attached to the cone by a cord.
Once the prey is paralyzed, the gastropod retracts the cord and engulfs the prey through the radular opening into its distensible stomach. Some cone species, such as C geographus, may distend and “net” prey with their “false mouths” before injecting venom. Digestion occurs over the ensuing several hours.
Cone shell toxins efficiently and highly selectively inhibit an extensive array of ion channels, receptors, and transporters involved in the transmission of neuromuscular signals in animals. The high target specificity of certain conotoxins toward mammalian channels is due to the fact that mammalian receptor isoforms of the specific target (eg, the nicotine receptor) are quite similar in sequence to their physiologic homologue in fish.
In the last few decades, these toxins have become the focus of some exciting molecular biological and pharmacological research. Conus venoms are remarkably diverse among species, and the large gene families that encode conotoxins show high evolutionary rates. A 2008 study suggests that this may result from either lineage-specific dietary modifications or differences in the positive impact of predator-prey interactional selection. [12, 13] To date, conotoxins have been divided into seven superfamilies, based on their disulfide bond frameworks, and they have been further divided into families based on their mechanisms of action. Several conotoxins, and their synthetic derivatives, due to their high selectivity and affinity for different ion channels, are the subjects of current clinical trials on chronic pain control, posttraumatic neuroprotection, cardioprotection, and the treatment of Parkinson disease and other neuromuscular disorders. [14]
While an extensive discussion of all discovered types of conotoxins and their specific activities is beyond the scope of this article and has served as the basis of several extensive reviews (see References), a sample of several distinct types of conotoxins and their effects are as follows:
Cone shells are prized by shell collectors for their pleasing shape and beautiful shells, which exhibit varying, intricate, darker geometric patterns on a lighter base. A sting most commonly occurs on the hand and/or fingers of an unsuspecting handler as well as on the feet of swimmers in shallow, tropical waters. Envenomations may also occur at contact points of collection bags. Even when picked up by the spire, the cone proboscis can rapidly extend more than a shell length to envenomate the unsuspecting shell handler. Cone radulae can penetrate a 5-mm neoprene wet suit.
At the site of envenomation, local stinging is followed within minutes by numbness, paresthesias, and ischemia. The actual puncture wound may not be evident. Serious envenomations may result in nausea, cephalgia, slurred speech, drooling, ptosis, diplopia and blurred vision, generalized paralysis, coma, and respiratory failure within hours. Death is typically secondary to diaphragmatic paralysis or cardiac failure. [16] C geographus, which produces the most potent conotoxins found to date, may produce rapid cerebral edema, coma, respiratory arrest, and cardiac failure. In significant envenomations, symptoms may take several weeks to resolve. Disseminated intravascular coagulation (DIC) may also be evident. The wound may be contaminated with marine organisms and can ulcerate and abscess. [17]
The following may lead to envenomation:
Careless or unknowledgeable handling of a hazardous specimen
Unsuspecting scuba divers carrying live cone shells in a wet suit, unsecured specimen bag, or buoyancy control device
Accidental contact while walking, swimming, and/or diving in shallow, tropical waters
Increased opportunities for exposure (eg, in aquarium keepers and handlers)
United States
Conus species are not indigenous to US waters. These are more likely to be encountered while traveling abroad, by specialized aquarium staff, or by researchers studying the venom components.
International
Thirty-one human envenomations have been documented in Southern Australia, the Indo-Pacific area, the islands of the Indian Ocean, and the Brazilian coast of the Atlantic Ocean. Many unreported envenomations may have occurred.
No relationship to age, race, or sex exists in Conus envenomation. Envenomation is more an injury of individuals engaged in either recreational or commercial shell collecting, diving, and fishing.
A high risk of death is associated with envenomation by certain species of cones, particularly C geographus, C textile, and C marmoreus. Morbidity includes mild symptoms (eg, nausea, weakness, diplopia) lasting several hours. Death has been documented within 5 hours in a C geographus envenomation. Two to 3 weeks of symptoms may be associated with more severe exposures. [18] In those who develop ulcerations at the site of envenomation, longer-term wound care may be required.
To assist in preventing cone shell envenomation, give patients the following instructions:
For patient education resources, visit the First Aid and Injuries Center. Also, see the patient education article Stingray Injury.
Lavergne V, Harliwong I, Jones A, et al. Optimizing deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks. Proceedings of the National Academy of Sciences of the United States of America. Available at http://www.pnas.org/content/112/29/E3782.full. July 6, 2015; Accessed: March 6, 2017.
Gorson J, Holford M. Small Packages, Big Returns: Uncovering the Venom Diversity of Small Invertebrate Conoidean Snails. Integr Comp Biol. 2016 Jul 1. [Medline].
Puillandre N, Duda TF, Meyer C, Olivera BM, Bouchet P. One, four or 100 genera? A new classification of the cone snails. J Molluscan Stud. 2015 Feb. 81 (1):1-23. [Medline].
Layer RT, Wagstaff JD, White HS. Conantokins: peptide antagonists of NMDA receptors. Curr Med Chem. 2004 Dec. 11 (23):3073-84. [Medline].
Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, et al. Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc Natl Acad Sci U S A. 2015 Feb 10. 112 (6):1743-8. [Medline].
Menting JG, Gajewiak J, MacRaild CA, Chou DH, Disotuar MM, Smith NA, et al. A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. Nat Struct Mol Biol. 2016 Oct. 23 (10):916-920. [Medline].
Dutertre S, Jin AH, Vetter I, Hamilton B, Sunagar K, Lavergne V, et al. Evolution of separate predation- and defence-evoked venoms in carnivorous cone snails. Nat Commun. 2014 Mar 24. 5:3521. [Medline].
Halford ZA, Yu PY, Likeman RK, Hawley-Molloy JS, Thomas C, Bingham JP. Cone shell envenomation: epidemiology, pharmacology and medical care. Diving Hyperb Med. 2015 Sep. 45 (3):200-7. [Medline].
Phuong MA, Mahardika GN. Targeted sequencing of venom genes from cone snail genomes improves understanding of conotoxin molecular evolution. Mol Biol Evol. 2018 Mar 5. [Medline].
Hu H, Bandyopadhyay PK, Olivera BM, Yandell M. Elucidation of the molecular envenomation strategy of the cone snail Conus geographus through transcriptome sequencing of its venom duct. BMC Genomics. 2012 Jun 28. 13:284. [Medline].
Yuan DD, Liu L, Shao XX, Peng C, Chi CW, Guo ZY. Isolation and cloning of a conotoxin with a novel cysteine pattern from Conus caracteristicus. Peptides. 2008 Sep. 29(9):1521-5. [Medline].
Phuong MA, Mahardika GN, Alfaro ME. Dietary breadth is positively correlated with venom complexity in cone snails. BMC Genomics. 2016 May 26. 17:401. [Medline].
Duda TF Jr. Differentiation of venoms of predatory marine gastropods: divergence of orthologous toxin genes of closely related Conus species with different dietary specializations. J Mol Evol. 2008 Sep. 67(3):315-21. [Medline].
Han TS, Teichert RW, Olivera BM, Bulaj G. Conus venoms- a rich source of peptide-based therapeutics. Current Pharmaceutical Design. 2008. 14(24):2462-79. [Medline].
Ekberg J, Craik DJ, Adams DJ. Conotoxin modulation of voltage-gated sodium channels. Int J Biochem Cell Biol. 2008. 40(11):2363-8. [Medline].
Kapil S, Cooper JS. Toxicity, Cone Snails. 2018 Jan. [Medline]. [Full Text].
Veraldi S, Violetti SA, Serini SM. Cutaneous abscess after Conus textile sting. J Travel Med. 2011 May-Jun. 18 (3):210-1. [Medline].
Kohn AJ. Human injuries and fatalities due to venomous marine snails of the family Conidae. Int J Clin Pharmacol Ther. 2016 Jul. 54 (7):524-38. [Medline].
Brown CK, Shepherd SM. Marine trauma, envenomations, and intoxications. Emerg Med Clin North Am. 1992 May. 10(2):385-408. [Medline].
Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM Professor of Emergency Medicine, Education Officer, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine; Medical Director, Fast Track, Department of Emergency Medicine
Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, Wilderness Medical Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
James Steven Walker, DO, MS Clinical Professor of Surgery, Department of Surgery, University of Oklahoma College of Medicine
James Steven Walker, DO, MS is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Osteopathic Emergency Physicians, American Osteopathic Association
Disclosure: Nothing to disclose.
Joe Alcock, MD, MS Associate Professor, Department of Emergency Medicine, University of New Mexico Health Sciences Center
Joe Alcock, MD, MS is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.
Samuel M Keim, MD, MS Professor and Chair, Department of Emergency Medicine, University of Arizona College of Medicine
Samuel M Keim, MD, MS is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Public Health Association, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
William H Shoff, MD, DTM&H Former Director, PENN Travel Medicine; Former Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine
William H Shoff, MD, DTM&H is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, Wilderness Medical Society
Disclosure: Nothing to disclose.
Conidae
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