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Niharika Mandal et al. / Journal of Pharmacy Research 2012,5(7),3567-3570

Review Article ISSN: 0974-6943

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Tetrodotoxin: An intriguing molecule

Niharika Mandal*, Samanta Sekhar Khora, Kanagaraj Mohanapriya, and Soumya Jal

School of Biosciences and T e chnology, VIT University, V e llore-632013 T a mil Nadu, India

Received on:07-04-2012; Revised on: 12-05-2012;Accepted on:16-06-2012

ABSTRACT

Tetrodotoxin (TTX) is one of the most potent neurotoxin of biological origin. It was first isolated from puffer fish and it has been discovered in various arrays of organism since then. Its origin is still unclear though some reports indicate towards microbial origin. TTX selectively blocks the sodium channel, inhibiting action potential thereby, leading to respiratory paralysis. TTX toxicity is mainly caused due to consumption of puffer fish. No Known antidote for TTX exists. Treatment is symptomatic. The present review is therefore, an effort to give an idea about the distribution, origin, structure, pharmacology, toxicity, symptoms, treatment, resistance and application of TTX.

Key words: Tetrodotoxin, Neurotoxin, Puffer fish.

INTRODUCTION

One of the most intriguing biotoxins isolated and described in the twentieth cantly more toxic than TTX. Palytoxin and maitotoxin have potencies nearly century is the neurotoxin, Tetrodotoxin (TTX, CAS Number [4368-28-9]). 100 times that of TTX and Saxitoxin, and all four toxins are unusual in being A neurotoxin is a toxin that acts specifically on neurons usually by interact- non-proteins. Interestingly, there is also some evidence for a bacterial bioing with membrane proteins and ion channels mostly resulting in paralysis. genesis of saxitoxin, palytoxin, and maitotoxin in living animals the toxin TTX is a poison so lethal that the US Food and Drug Administration warn acts primarily on myelinated (sheathed) peripheral nerves and does not it can lead to “rapid and violent death”. It is named after the order of fish appear to cross the blood-brain barrier.” from which it is most commonly associated, the Tetraodontiformes. The member of this order includes the various types of puffer fish. It was first Distribution isolated in 1909 from Spheroides rubripes (puffer fish).[1] Pure crystalline A total of 22 species of puffers in the family tetraodontidae are reported to form of TTX was isolated in 1950 from the overies of Fugu rubripes  contain TTX, [8] while the closely related porcupine fish and boxfish does (puffer fish).[2] TTX was believed to occur only in puffer fish for a long not contain TTX. TTX is accumulated in the liver, gonads, intestine, muscle time, however the toxin has been found in a variety of animals. The toxin is and skin of the puffer fish.[9-10] The distribution of TTX in puffer fish varies variously used as a defensive biotoxin to ward off predation as in case of between species and at different seasons and geographic localities. Other puffer fish,[3] or as both defensive and predatory venom like in the case of marine organisms which contain TTX are worms such as Lineus Fuscoviridis blue ringed octopus.[4-6]

annelids like Pseudopolamilla occelata, Snails like Charonia and Niotha, Crustaceans like horseshoe crab (Carcinoscorpius rotundicauda) as well
TTX is a non protienaceous low molecular weight (319.28 amu) neuro- as Xanthid Crabs of different genera, starfish of genus Astropecte, goby fish

toxin. TTX is highly polar and hygroscopic and is only sparingly soluble in (Y o ngeichthys criniger) etc. Some blue-ringed octopuses of genus acidified water. It has a pk of 8.5. A single milligram or less of TTX - an Hapalochlaena contain TTX in their posterior salivary glands and soft amount that can be placed on the head of a pin, is enough to kill an adult . tissues.[6] Some terrestrial vertebrates like Californian newts (Taricha torosa)

  • The LD50 of TTX for human is 10.2µg/kg. [7]
  • and frogs from genus Atelopus were also reported to contain TTX.[11-12] This

highly potent neurotoxin is found in a diverse array of organisms, including
According to William H. Light, “Tetrodotoxin is ten times as deadly as the bacteria, dinoflagellates, arthropods, nematodes, mollusks, fish, and amvenom of the many-banded krait of Southeast Asia. It is 10 to 100 times as phibians. The number of species containing TTX continues to grow. lethal as black widow spider venom (depending upon the species) when administered to mice, and more than 10,000 times deadlier than cyanide. It Origin has the same toxicity as saxitoxin which causes paralytic shellfish poison- The metabolic source of TTX is still uncertain. Until now TTX was being ([both TTX and saxitoxin block the Na+ channel - and both are found in lieved to be produced by the animal (or the host). However, recent reports the tissues of puffer fish]) A recently discovered, naturally occurring con- point towards the bacterial origin of this toxin TTX is considered likely to gener of tetrodotoxin has proven to be four to five times as potent as TTX. be produced by marine bacteria associated with marine animals. The most Except for a few bacterial protein toxins, only palytoxin, a bizarre molecule common TTX producing bacteria are Vibrio bacteria, with Vibrio isolated from certain zoanthideans (small, colonial, marine organisms re- alginolvticus being the most common species. Puffer fish,[13] sembling sea anemones) of the genus Palythoa, and maitotoxin, found in Chaetognathas,[14] and Nemerteans,[15] have been shown to contain and Vibrio certain fishes associated with ciguatera poisoning, are known to be signifi- alginolvticus TTX. These TTX producing bacteria are primarily marine species,[16-19] although a few freshwater species have also been identified.[20] A vast array of taxonomic groups is known to possess TTX.[21-23] This is unusual for animal toxins, as they are usually very specific for a particular

*Corresponding author.

Niharika Mandal

group. In marine organisms the accepted hypothesis is that the TTX present

Research Associate

in metazoans results from either dietary uptake of bacterially produced

School of Biosciences and Technology Medical Biotechnology Laboratory SMV 203, VIT University, Vellore 632013,T a mil Nadu, India

TTX or symbiosis with TTX producing bacteria.[22-26] However this hypothesis is not acceptable for TTX present in terrestrial taxa.[21, 27-30] This is probably because TTX in terrestrial metazoans appears to be limited to a

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single class of vertebrates (Amphibia) with limited distributions within the

Tetrodotoxin Toxicity

class, unlike marine species in which TTX is found in a wide array of taxa. Moreover, the presence of multiple analogs of TTX are common in the TTX profiles of some TTX bearing amphibians, but are absent or a very minor component in the TTX profiles of marine taxa or TTX producing bacteria.[31-37] Therefore, several genera of bacteria have been identified as TTX producers,[19, 26, 38] but these findings are controversial.[39-41]The production of TTX in animals has not been firmly established, and there remains much debate in the literature as to whether the bacteria are truly the source of TTX in animals.
The first recorded case of tetrodotoxin poisoning was on 7 September 1774,[1] when Captain James Cook recorded his crew eating some local tropic fish (puffer fish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. It was clear that the crew received a mild dose of tetrodotoxin, while the pigs ate the puffer fish body parts that contain most of the toxin, thus being fatally poisoned. Tetrodotoxin toxicity mostly occurs due to the consumption of puffer fish. The organs (e.g. liver) of the puffer fish can contain levels of tetrodotoxin sufficient to produce paralysis of the diaphragm and death due to respiratory failure,[1] On the other hand, puffer fish is considered as a notorious delicacy in Japan. It is prepared by chefs who are specially trained and certified by the government. Despite these precautions, many cases of tetrodotoxin poisoning are reported each year in patients ingesting puffer fish.

Structure

The structure of TTX was first elucidated in 1964 at the Natural Product Symposium of the International Union of Pure applied Chemistry by four different Lab groups including K. Tsuda, T. Goto, R.B. Woodward and H.S. Mosher.[42] TTX has a guanidium ion with a complex oxygenated cyclohexane framework with both guanidine and orth-oacid functional groups. [43-45] Numerous natural, synthetic and semi-synthetic analogs of TTX have been reported. Amphibians have been a plentiful source of TTX analogs.[31-32, 46-
TTX is not always fatal, but at near-lethal doses, it can leave a person in a state of near-death for several days, while the person remains conscious. That is why, TTX has been used an ingredient in Haitian Vodou and the closest approximation of zombieism, an idea popularized by Harvardtrained ethnobotanist Wade Davis in a 1983 paper, and in his 1985 book, The Serpent and the Rainbow. This idea was dismissed by the scientific community in the 1980s, as the descriptions of voodoo zombies do not match the symptoms displayed by victims of tetrodotoxin poisoning, and the alleged incidents of zombies created in this manner could not be substantiated.[58]

48]

The hemilactal forms of TTX are more common naturally occurring analogs. These analogs are very potent and have toxicities equivalent or greater than TTX itself. [47-51] The structure and analogs of TTX are shown in Fig1.

Pharmacology

The pharmacology of TTX was studied by Takahashi in 1889,[42] but, it was not until 1950’s that more detailed understanding of the pharmacology of TTX began to emerge. TTX was shown to block sodium channels in excitable membranes.[52-54] It is found that TTX binds and blocks voltage gated sodium channels with very high specificity (Kd = 10-10 nM), thereby

Symptoms

Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours however; death within 17 minutes of ingestion

  • has also been recorded.[1] The first symptom of intoxication is a slight
  • preventing the influx of sodium ions. The positively charged amino end of

TTX forms complex electrostatic bonds with two charged rings of amino numbness of the lips and tongue.[1] followed by paresthesia in face and

  • acid residues in the outer pore of the sodium channel. [55-57]
  • extremities, sweating, headache, weakness, lethargy, incoordination, tremor,

paralysis, cyanosis, aphonia, dysphagia, seizures, dyspnea, bronchorrhea,
The flow of sodium ions into nerve cells is a necessary step in the conducbronchospasm, respiratory failure, coma, and hypotension. Gastroenteric tion of nerve impulses in excitable nerve fibers and along axons. Normal symptoms are often severe and include nausea, vomiting, diarrhea, and axon cells have high concentrations of K+ ions and low concentrations of abdominal pain. Cardiac arrhythmias may precede complete respiratory
Na+ ions and have a negative potential. Stimulation of the axon results in an failure and cardiovascular collapse. If the patient survives 24 hours, recovaction potential which arises from a flow of Na+ions into the cell and the ery without any residual effects usually occurs over several days. generation of a positive membrane potential. Propagation of this depolar-

ization along the nerve terminal presages all other events. The Na+ ions

Treatment

flow through the cellular membrane employing the sodium ion channel, a
No known antidote for TTX poisoning exists. Treatment is symptomatic channel that is selective for sodium ions over potassium ions by an order with aggressive early airway management, it includes emptying the stomof magnitude. Tetrodotoxin is quite specific in blocking the Na+ ion channel ach, feeding the victim activated charcoal to bind the toxin, and taking stanand therefore the flow of Na+ ions while having no effect on dard life-support measures to keep the victim alive until the effect of the
K+ ions. Tetrodotoxin competes with the hydrated sodium cataion and enpoison has worn off.[1] Alpha adrenergic agonists are recommended in additers the Na+-channel where it binds. The hydrated sodium ion binds retion to intravenous fluids to combat hypotension. Anticholinesteraseagents versibly on a nanosecond time-scale, whereas TTX is bound for tens of have been used with mixed success. A monoclonal antibody specific to seconds. With the bulk of the TTX molecule denying sodium the opportutetrodotoxin has been developed and was shown to be effective for reducing nity to enter the channel, sodium movement is effectively shut down, and lethality in murine tests.[59] the action potential along the nerve membrane ceases.

Resistance to TTX

Saxitoxin and several of the conotoxins also bind the same site. Compared
An obvious question is, since TTX is so lethal, then how do animals like the with saxitoxin, Tetrodotoxin is slightly less neuroactive but has more propuffer fish and Taricha newts that accumulate it in large concentrations in longed effects. It is less easily reversed and creates small transient potentiatheir bodies remain unaffected? This is because Puffers have evolved with tion of maximal muscular contraction with subliminal doses. Tetrodotoxin a slightly different sodium channel which still allows sodium ion to pass has less effect on muscle fiber (saxitoxin can cause neuromuscular muscle through without becoming inhibited by TTX. It is due to the key substituweakness without hypotension); however it causes hypotension via effect tions of amino acids which modify the sodium channel thereby, reducing on the vasomotor tone through preganglionic fibers or direct action on the affinity to the toxin and allowing the channels to function normally.[60] cardiac muscle.
Similar to puffer fish resistance newts have also developed resistance due

to conformational change in the sodium channel.[21] Interestingly,

garter snakes (Thamnophis sirtalis) that prey on the newt Taricha have

Journal of Pharmacy Research Vol.5 Issue 7.July 2012
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Niharika Mandal et al. / Journal of Pharmacy Research 2012,5(7),3567-3570

also acquired TTX resistance.[61-62] Snakes from populations that do not encounter the newts in the wild, however, are poisoned when fed newts in the laboratory, indicating a co-evolutionary interaction between the preda-
11. Wakely JF, Fuhrman GJ, Fuhrman FA, Fischer HG, Mosher HS,
The occurrence of tetrodotoxin (tarichatoxin) in amphibia and the distribution of the toxin in the organs of newts (Taricha). Toxicon 1996, 3,195-203.

[7]

tor and its prey.
12. Yamashita MY, Mebs D, Yasumoto T, Tetrodotoxin and its analogues in extracts from the toad Atelopus oxyrhynchus (family: Bufonidae). Toxicon, 1992, 30,1489-1492.

Application of TTX

The use of TTX as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na+ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+ channel). Tetrodotoxin binds to TTX-s Na+ channels with a very high binding affinity, while the TTX-r Na+ channels bind TTX with very low affinity. Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+ channels dominate the rest of the body. The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture. Tetrodotoxin has been one of the most widely used tools for selective blockade of sodium channels in neurophysiology. Blocking of fast Na+ channels has potential medical use in treating some cardiac arrhythmias. TTX is a potent analgesic and it has been proved useful in the treatment of pain due to cancer,[63] and migraines. It also serves as an effective agent in detoxification from heroin addiction without withdrawal symptoms and without producing physical dependence.[64]
13. Noguchi T, Hwang DF, Arakawa O, Sugita H, Deguchi Y, Shida Y,
Hashimoto K, Vibrio alginolyticus, a tetrodotoxin-producing bacterium, in the intestines of the fish Fugu vermicularis vermicularis. Marine Biology, 1987, 94,625–630.
14. Thuesen EV, Kogure K, Bacterial production of tetrodotoxin in four species of Chaetognatha”. Biological Bulletin, 176, 1989, 191–194.
15. Carroll S, McEvoy EG, Gibson R, The production of tetrodotoxin-like substances by nemertean worms in conjunction with bacteria. Journal of experimental marine biology and ecology, 2003, 288,51–63.
16. Do HK, Kogure K, Simidu U, Identification of deep-seasediment bacteria which produce tetrodotoxin. Applied and Environmental Microbiology 1990, 56, 1162–1163.
17. Kogure K, Do HK, Thuesen EV, Nanba K, Ohwada K, Simidu U,
Accumulation of tetrodotoxin in marine sediment. Marine Ecology Progr. Ser., 1988, 45, 303–305.
18. Ritchie KB, Nagelkerken I, James S, Smith GW, A tetrodotoxinproducing marine pathogen. Nature, 2000, 404, 354.
19. Simidu U, Noguchi T, Hwang DF., Shida Y, Hashimoto K, Marine bacteria which produce tetrodotoxin. Applied and Environmental Microbiology, 1987, 53, 1714–1715.

CONCLUSION

Tetrodotoxin is a unique biomolecule. It has always been a topic of interest for the scientists in the past as well as in the present. TTX has been studied extensively yet its origin remains unclear. No antidote for TTX has been found yet. These are the few areas in which research has to be focused.
20. Do HK, Hamasaki K, Ohwada K, Simidu U, Noguchi T, Shida Y,
Kogure K, Presence of tetrodotoxin and tetrodotoxin-producing bacteria in fresh-water sediments. Applied and Environmental Microbiology, 1993, 59, 3934–3937.

ACKNOWLEDGEMENT

We express our gratitude towards everyone in the School of Biosciences and Technology, VIT University.
21. Daly JW, Marine toxins and nonmarine toxins: Convergence or symbiotic organisms. J Nat Prod., 2004, 67, 1211–1215.
22. Miyazawa K, Noguchi T, Distribution and origin of tetrodotoxin. J
Toxicol: Toxin Rev., 2001, 20,11–33.
23. Noguchi T, Arakawa O, Tetrodotoxin—distribution and accumulation in aquatic organisms, and cases of human intoxication. Mar Drugs., 2008, 6,220–242.
24. Do HK, Kogure K, Simidu U, Identification of deep-sea-sediment bacteria which produce tetrodotoxin. Appl Environ Microbiol., 1990, 56, 1162–1163.
25. Noguchi T, Jeon JK, Arakawa O, Sugita H, Deguchi Y, Shida Y,
Hashimoto K, Occurrence of tetrodotoxin and anhydrotetrodotoxin in Vibrio sp. isolated from the intestines of a xanthid crab Atergatis floridus. J Biochem. 1986, 99, 311–314
26. Yasumoto T, Yasumura D, Yotsu M, Michishita T, Endo A, Kotaki
Y, Bacterial production of tetrodotoxin and anhydrotetrodotoxin. Agric Biol Chem. 1986, 50, 793–795.
27. Daly JW, Myers CW, Whittaker N, Further classification of skin alkaloids from neotropical poison frogs (Dendrobatidae), with a general survey of toxic/noxious substances in the amphibia. Toxicon, 1987, 25, 1023–1095.
28. Cardall BL, Brodie ED, Jr, Brodie ED, III, Hanifin CT, Secretion and regeneration of tetrodotoxin in the rough-skin newt (T a richa granulosa) Toxicon, 2004, 44, 933–938.
29. Hanifin CT, Brodie ED, III, Brodie ED, Jr, Tetrodotoxin levels of the rough-skin newt, Taricha granulosa, increase in long-term captivity. Toxicon, 2002, 40, 1149–1153.
30. Lehman EM, Brodie ED, Jr, Brodie ED, III, No evidence for an endosymbiotic bacterial origin of tetrodotoxin in the newt Taricha granulosa. Toxicon, 2004, 44, 243–249.

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    Entry Amanita muscaria: Ecology, Chemistry, Myths Quentin Carboué * and Michel Lopez URD Agro-Biotechnologies Industrielles (ABI), CEBB, AgroParisTech, 51110 Pomacle, France; [email protected] * Correspondence: [email protected] Definition: Amanita muscaria is the most emblematic mushroom in the popular representation. It is an ectomycorrhizal fungus endemic to the cold ecosystems of the northern hemisphere. The basidiocarp contains isoxazoles compounds that have specific actions on the central nervous system, including hallucinations. For this reason, it is considered an important entheogenic mushroom in different cultures whose remnants are still visible in some modern-day European traditions. In Siberian civilizations, it has been consumed for religious and recreational purposes for millennia, as it was the only inebriant in this region. Keywords: Amanita muscaria; ibotenic acid; muscimol; muscarine; ethnomycology 1. Introduction Thanks to its peculiar red cap with white spots, Amanita muscaria (L.) Lam. is the most iconic mushroom in modern-day popular culture. In many languages, its vernacular names are fly agaric and fly amanita. Indeed, steeped in a bowl of milk, it was used to Citation: Carboué, Q.; Lopez, M. catch flies in houses for centuries in Europe due to its ability to attract and intoxicate flies. Amanita muscaria: Ecology, Chemistry, Although considered poisonous when ingested fresh, this mushroom has been consumed Myths. Encyclopedia 2021, 1, 905–914. as edible in many different places, such as Italy and Mexico [1]. Many traditional recipes https://doi.org/10.3390/ involving boiling the mushroom—the water containing most of the water-soluble toxic encyclopedia1030069 compounds is then discarded—are available. In Japan, the mushroom is dried, soaked in brine for 12 weeks, and rinsed in successive washings before being eaten [2].
  • Swaminathan (Article)

    Swaminathan (Article)

    © 2000 Nature America Inc. • http://structbio.nature.com articles Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B Subramanyam Swaminathan and Subramaniam Eswaramoorthy Clostridium botulinum neurotoxins are among the most potent toxins to humans. The crystal structures of intact C. botulinum neurotoxin type B (BoNT/B) and its complex with sialyllactose, determined at 1.8 and 2.6 Å resolution, respectively, provide insight into its catalytic and binding sites. The position of the belt region in BoNT/B is different from that in BoNT/A; this observation presents interesting possibilities for designing specific inhibitors that could be used to block the activity of this neurotoxin. The structures of BoNT/B and its complex with sialyllactose provide a detailed description of the active site and a model for interactions between the toxin and its cell surface receptor. The latter may provide valuable information for recombinant vaccine development. Botulinum and tetanus neurotoxins are solely responsible for the neuroparalytic syndromes of botulism and tetanus. These toxins .com are among the most poisonous known, with LD50 values in humans in the range of 0.1–1 ng kg-1 (ref. 1). Clostridium botu- linum cells produce seven serotypes of botulinum neurotoxin (BoNT, EC 3.4.24.69), called A–G, while tetanus neurotoxin (TeNT, EC 3.4.24.68) is produced by Clostridium tetani. These toxins are all produced as single inactive polypetide chains of ∼150 kDa that are cleaved by tissue proteinases into two chains: a heavy (H) chain of ∼100 kDa and a light (L) chain of ∼50 kDa http://structbio.nature • linked by a single disulfide bond.
  • Saxitoxin and ,U-Conotoxins (Brain/Electric Organ/Heart/Tetrodotoxin) EDWARD MOCZYDLOWSKI*, BALDOMERO M

    Saxitoxin and ,U-Conotoxins (Brain/Electric Organ/Heart/Tetrodotoxin) EDWARD MOCZYDLOWSKI*, BALDOMERO M

    Proc. Nati. Acad. Sci. USA Vol. 83, pp. 5321-5325, July 1986 Neurobiology Discrimination of muscle and neuronal Na-channel subtypes by binding competition between [3H]saxitoxin and ,u-conotoxins (brain/electric organ/heart/tetrodotoxin) EDWARD MOCZYDLOWSKI*, BALDOMERO M. OLIVERAt, WILLIAM R. GRAYt, AND GARY R. STRICHARTZt *Department of Physiology and Biophysics, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267-0576; tDepartment of Biology, University of Utah, Salt Lake City, UT 84112; and tAnesthesia Research Laboratories and the Department of Pharmacology, Harvard Medical School, Boston, MA 02115 Communicated by Norman Davidson, March 17, 1986 ABSTRACT The effect oftwo pL-conotoxin peptides on the 22 amino acids with amidated carboxyl termini (18). One of specific binding of [3H]saxitoxin was examined in isolated these toxins, GIIIA, has recently been shown to block muscle plasma membranes of various excitable tissues. pt-Conotoxins action potentials (18) and macroscopic Na current in a GITIA and GIHIB inhibit [3H]saxitoxin binding inlEkctrophorus voltage-clamped frog muscle fiber (19). At the single channel electric organ membranes with similar Kds of %50 x 10-9 M level, the kinetics of GIIIA block have been shown to in a manner consistent with direct competition for a common conform to a single-site binding model (Kd, 110 x 10-9 M at binding site. GITIA and GIIIB similarly compete with the 0 mV), from analysis of the statistics of discrete blocking majority (80-95%) of [3Hlsaxitoxin binding sites in rat skeletal events induced in batrachotoxin-activated Na channels from muscle with Kds of -25 and "140 x 10-9 M, respectively.
  • A Review of Chemical Defense in Poison Frogs (Dendrobatidae): Ecology, Pharmacokinetics, and Autoresistance

    A Review of Chemical Defense in Poison Frogs (Dendrobatidae): Ecology, Pharmacokinetics, and Autoresistance

    Chapter 21 A Review of Chemical Defense in Poison Frogs (Dendrobatidae): Ecology, Pharmacokinetics, and Autoresistance Juan C. Santos , Rebecca D. Tarvin , and Lauren A. O’Connell 21.1 Introduction Chemical defense has evolved multiple times in nearly every major group of life, from snakes and insects to bacteria and plants (Mebs 2002 ). However, among land vertebrates, chemical defenses are restricted to a few monophyletic groups (i.e., clades). Most of these are amphibians and snakes, but a few rare origins (e.g., Pitohui birds) have stimulated research on acquired chemical defenses (Dumbacher et al. 1992 ). Selective pressures that lead to defense are usually associated with an organ- ism’s limited ability to escape predation or conspicuous behaviors and phenotypes that increase detectability by predators (e.g., diurnality or mating calls) (Speed and Ruxton 2005 ). Defended organisms frequently evolve warning signals to advertise their defense, a phenomenon known as aposematism (Mappes et al. 2005 ). Warning signals such as conspicuous coloration unambiguously inform predators that there will be a substantial cost if they proceed with attack or consumption of the defended prey (Mappes et al. 2005 ). However, aposematism is likely more complex than the simple pairing of signal and defense, encompassing a series of traits (i.e., the apose- matic syndrome) that alter morphology, physiology, and behavior (Mappes and J. C. Santos (*) Department of Zoology, Biodiversity Research Centre , University of British Columbia , #4200-6270 University Blvd , Vancouver , BC , Canada , V6T 1Z4 e-mail: [email protected] R. D. Tarvin University of Texas at Austin , 2415 Speedway Stop C0990 , Austin , TX 78712 , USA e-mail: [email protected] L.
  • Evidence That Tetrodotoxin and Saxitoxin Act at a Metal Cation Binding Site in the Sodium Channels of Nerve Membrane (Solubilized Membrane/Receptors/Surface Charge) R

    Evidence That Tetrodotoxin and Saxitoxin Act at a Metal Cation Binding Site in the Sodium Channels of Nerve Membrane (Solubilized Membrane/Receptors/Surface Charge) R

    Proc. Nat. Acad. Sci. USA 71 Vol. 71, No. 10, pp. 3936-3940, October 1974 Evidence That Tetrodotoxin and Saxitoxin Act at a Metal Cation Binding Site in the Sodium Channels of Nerve Membrane (solubilized membrane/receptors/surface charge) R. HENDERSON*, J. M. RITCHIE, AND G. R. STRICHARTZt Departments of Molecular Biophysics and Biochemistry, and of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 Communicated by Frederic M. Richards, June 17, 1974 ABSTRACT The effects of monovalent, divalent, and STX. These experiments suggest how the toxins exert their trivalent cations on the binding of tetrodotoxin and saxi- toxin to intact nerves and to a preparation of solubilized action, and provide a unifying explanation of how several nerve membranes have been examined. All eight divalent cations affect nerve membrane permeability. and trivalent cations tested, and the monovalent ions MATERIALS AND LiW, Tl+, and H+ appear to compete reversibly with the METHODS toxins for their binding site. The ability of lithium to Tritium-labeled TTX and STX were prepared and purified reduce toxin binding is paralleled by its ability to reduce (3, 5). Olfactory nerves from garfish, obtained from the Gulf tetrodotoxin-sensitive ion fluxes through the nerve mem- brane. We conclude that the toxins act at a metal cation Specimen Co., Florida, were dissected by the method of binding site in the sodium channel and suggest that this Easton (12). A detergent-solubilized extract of the nerves site is the principal coordination site for cations (normally was prepared by the method of Henderson and Wang (4). Na+ ions) as they pass through the membrane during an Binding experiments were also carried out on intact garfish action potential.
  • Alcohol Dependence and Withdrawal Impair Serotonergic Regulation Of

    Alcohol Dependence and Withdrawal Impair Serotonergic Regulation Of

    Research Articles: Cellular/Molecular Alcohol dependence and withdrawal impair serotonergic regulation of GABA transmission in the rat central nucleus of the amygdala https://doi.org/10.1523/JNEUROSCI.0733-20.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.0733-20.2020 Received: 30 March 2020 Revised: 8 July 2020 Accepted: 14 July 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Alcohol dependence and withdrawal impair serotonergic regulation of GABA 2 transmission in the rat central nucleus of the amygdala 3 Abbreviated title: Alcohol dependence impairs CeA regulation by 5-HT 4 Sophia Khom, Sarah A. Wolfe, Reesha R. Patel, Dean Kirson, David M. Hedges, Florence P. 5 Varodayan, Michal Bajo, and Marisa Roberto$ 6 The Scripps Research Institute, Department of Molecular Medicine, 10550 N. Torrey Pines 7 Road, La Jolla CA 92307 8 $To whom correspondence should be addressed: 9 Dr. Marisa Roberto 10 Department of Molecular Medicine 11 The Scripps Research Institute 12 10550 N. Torrey Pines Road, La Jolla, CA 92037 13 Tel: (858) 784-7262 Fax: (858) 784-7405 14 Email: [email protected] 15 16 Number of pages: 30 17 Number of figures: 7 18 Number of tables: 2 19 Number of words (Abstract): 250 20 Number of words (Introduction): 650 21 Number of words (Discussion): 1500 22 23 The authors declare no conflict of interest.