- Author: Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM; Chief Editor: Joe Alcock, MD, MS more...
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 500 members of the invertebrate Conidae family of the phylum Mollusca (ie, the cone shells).
In the last 4 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. It has been estimated that as many as 50,000 venom components may be produced by the Conus genus. These venoms serve the cone as a primary weapon to capture prey, as defense, and possibly for other functions.
See Deadly Sea Envenomations, a Critical Images slideshow, to help make an accurate diagnosis.
Cone shells are carnivorous; they are divided into 3 groups, according to their prey items: molluscivorous (hunt other gastropods), vermivorous (hunters of polychaete and other worms), or piscivorous (fish hunting). The largest group of cones are molluscivorous. Their habitats extend from shallow, intertidal areas to extreme deep-water areas. They inhabit primarily tropical marine environments; however, a few species are found in cooler environments. Cone shells are predominantly nocturnal, burrowing in the sand and coral during the daytime.
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 paralytic and lethal oligopeptide toxins, each 15-30 residues long, into the prey.
Almost 200 different conotoxin peptides have been identified to date. These potent peptides target ion channels, either voltage- or ligand-gated receptors and transporters in excitable cells. The venom mixture is specific to each cone shell species, containing 30-200 conotoxin peptides. A group of conopeptides, described as a cabal, act in a coordinated manner to produce a specific physiologic endpoint such as inhibition of both voltage-gated sodium channel activation and potassium channel block, resulting in massive depolarization of axons at the injection site, causing an effect similar to electrocution of 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 spatial shape for each toxin, while non-conotoxin peptides lack multiple disulfides.
Thirty cases of human envenomation, with occasional fatalities, have been documented worldwide. Human envenomations have involved 18 species of cone shells, including Conus geographus, Conus catus, Conus aulicus, Conus gloria-maris, Conus omaria, Conus magus, Conus striatus, Conus tulipa, and Conus textile.
The cone shell detects its prey via the siphon, which is covered with chemoreceptors, although limited visual signaling may also be involved. Venom, formed in a venom duct, 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. 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 an extensible proboscis. The venom sac contains approximately 20 radula. The muscular proboscis, which may extend 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. 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. Other cone species, such as Conus 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 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 recent study suggests that this may result from either lineage-specific dietary modifications or differences in the positive impact of predator-prey interactional selection. To date, conotoxins have been divided into 7 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, post-traumatic neuroprotection, cardioprotection, and the treatment of Parkinson disease and other neuromuscular disorders.
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 found below.
W-conotoxin - Hinders the voltage-dependent entry of calcium into the nerve terminal and inhibits acetylcholine release
M-conotoxin - Modifies muscle sodium channels by occluding and thereby blocking ion conduction through the pore of voltage-gated sodium channels (VGSC), at the same site as saxitoxin and tetrodotoxin 
K-conotoxin - Potassium channel (VGPC)-targeting peptides
A-conotoxin - Blocks the nicotinic acetylcholine receptor, similarly to snake alpha-neurotoxins
G-conotoxin - Delays or inhibits VGSC inactivation, resulting in prolongation of the action potential; this produces a "hyperexcited state" in involved neurons and can lead to electrical hyperexcitation of the entire organism, eg, seizures in marine snails 
S-conotoxins - Inhibit 5-HT3 channels
Y-conotoxins - Competitively block muscle acetylcholine receptors
Conantokins - Target NMDA ( N -methyl-D-aspartate) subtype glutamate receptors
Conopressin - Vasopressin agonist
Sleeper peptide - Found primarily in C geographus, induces a deep sleep state in test animals
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. Local stinging is followed within minutes by numbness, paresthesias, and ischemia. Serious envenomations may result in nausea, cephalgia, generalized paralysis, coma, and respiratory failure within hours. Death is typically secondary to diaphragmatic paralysis or cardiac failure. 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.
Conus species are not indigenous to United States waters. These are more likely to be encountered while traveling abroad or by specialized aquarium staff.
Thirty human envenomations have been documented in Southern Australia and the Indo-Pacific area. Many unreported envenomations may have occurred.
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.
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.
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].
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].
Atanassoff PG, Hartmannsgruber MW, Thrasher J, Wermeling D, Longton W, Gaeta R, et al. Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med. 2000 May-Jun. 25(3):274-8. [Medline].
Auerbach PS. Marine envenomations. N Engl J Med. 1991 Aug 15. 325(7):486-93. [Medline].
Brown CK, Shepherd SM. Marine trauma, envenomations, and intoxications. Emerg Med Clin North Am. 1992 May. 10(2):385-408. [Medline].
Cox B. Calcium channel blockers and pain therapy. Curr Rev Pain. 2000. 4(6):488-98. [Medline].
Cruz LJ, White J. Clinical toxicology of Conus snail stings. Handbook of Clinical Toxicology of Animal Venoms and Poisons. CRC Press; 1995. 117-128.
Dutertre S, Lewis RJ. Toxin insights into nicotinic acetylcholine receptors. Biochem Pharmacol. 2006 Sep 14. 72(6):661-70. [Medline].
Hahin R, Wang GK, Shapiro BI, Strichartz G. Alterations in sodium channel gating produced by the venom of the marine mollusc Conus striatus. Toxicon. 1991. 29(2):245-59. [Medline].
Hawdon GM, Winkel KD. Venomous marine creatures. Aust Fam Physician. 1997 Dec. 26(12):1369-74. [Medline].
Heinemann SH, Leipold E. Conotoxins of the O-superfamily affecting voltage-gated sodium channels. Cell Mol Life Sci. 2007 Jun. 64(11):1329-40. [Medline].
Jain KK. An evaluation of intrathecal ziconotide for the treatment of chronic pain. Expert Opin Investig Drugs. 2000 Oct. 9(10):2403-10. [Medline].
Jin AH, Brandstaetter H, Nevin ST, Tan CC, Clark RJ, Adams DJ, et al. Structure of alpha-conotoxin BuIA: influences of disulfide connectivity on structural dynamics. BMC Struct Biol. 2007. 7:28. [Medline].
Kobayashi J, Nakamura H, Hirata Y, Ohizumi Y. Effect of venoms from Conidae on skeletal, cardiac and smooth muscles. Toxicon. 1982. 20(5):823-30. [Medline].
Livett BG, Sandall DW, Keays D, Down J, Gayler KR, Satkunanathan N, et al. Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor. Toxicon. 2006 Dec 1. 48(7):810-29. [Medline].
McIntosh JM, Jones RM. Cone venom--from accidental stings to deliberate injection. Toxicon. 2001 Oct. 39(10):1447-51. [Medline].
Miljanich GP. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004 Dec. 11(23):3029-40. [Medline].
Norton RS, Olivera BM. Conotoxins down under. Toxicon. 2006 Dec 1. 48(7):780-98. [Medline].
Olivera BM. Conotoxins and other biologically active peptides in Conus venoms. Toxicon. 1990. 28:256.
Olivera BM, Rivier J, Clark C, Ramilo CA, Corpuz GP, Abogadie FC, et al. Diversity of Conus neuropeptides. Science. 1990 Jul 20. 249(4966):257-63. [Medline].
Pi C, Liu J, Peng C, Liu Y, Jiang X, Zhao Y, et al. Diversity and evolution of conotoxins based on gene expression profiling of Conus litteratus. Genomics. 2006 Dec. 88(6):809-19. [Medline].
Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006 May. 31(5):393-406. [Medline].
Sharpe IA, Gehrmann J, Loughnan ML, Thomas L, Adams DA, Atkins A, et al. Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter. Nat Neurosci. 2001 Sep. 4(9):902-7. [Medline].
Teichert RW, Jacobsen R, Terlau H, Yoshikami D, Olivera BM. Discovery and characterization of the short kappaA-conotoxins: a novel subfamily of excitatory conotoxins. Toxicon. 2007 Mar 1. 49(3):318-28. [Medline].