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Review

From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules

1
Department of Biology, Faculty of Sciences, Arak University, Iran
2
Laboratory of Chemical Biology, Institut de Science et d'Ingénierie Supramoléculaires; ISIS/Université de Strasbourg, CNRS-UMR 7006, 8, allée Gaspard Monge, BP 70028, F-67083, Strasbourg Cedex, France
3
Laboratoire de Biophysicochimie des Récepteurs Canaux, UMR 7199 “Conception et Application de Molécules Bioactives” CNRS-Université de Strasbourg, 74 Route du Rhin-BP 60024, 67401 Illkirch Cedex, France
*
Author to whom correspondence should be addressed.
Toxins 2011, 3(3), 260-293; https://doi.org/10.3390/toxins3030260
Submission received: 8 November 2010 / Revised: 1 February 2011 / Accepted: 16 March 2011 / Published: 21 March 2011
(This article belongs to the Special Issue Toxins as Therapeutics)

Abstract

:
Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted.

1. Introduction and Scope of the Review

1.1. To be Poisonous or Not: The Dose Effect

When thinking of toxic compounds, researchers often have in mind the famous citation of Paracelsus (Philippus Theophrastus Aureolus Bombastus von Hohenheim): "The dose makes the poison" or in its more complete version "All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison." [1]. Although this 16th century concept is now debated, Paracelsus is still recognized as one of the fathers of "Toxicology" as it is envisioned today.
Medical drugs and toxins are good illustrations of this adage. On the one hand, medical drugs are often perceived as non-poisonous because of their potential benefit for humans. However, it is now well known that widely used drugs like Paracetamol℘ or Ibuprofen℘ can be highly toxic at relatively moderate doses [2]. On the other hand, toxins are generally perceived as dangerous for humans because of their possible accumulation in the alimentary chain or their use as biological weapons (e.g., anatoxin-a). However, following Paracelsus, lowering the dose might allow to make them non-toxic. Solving the issue of toxicity would pave the way to turn them into medicine. Indeed, in addition to their use as an invaluable source of ligands for studying structural or functional properties of their molecular targets [3], these molecules are now increasingly interesting to researchers for their use as medicine or cosmetic products [4].

1.2. Toxins as Biological Poisons

The word 'toxin' was first introduced by Ludwig Brieger as a name for poisons made by infectious agents [5]. These biological poisons allow the organisms to survive difficult environmental situations where the toxins are advantageous for prey capture or defense [6]. Plant toxins (e.g., nicotine) often function as protection against certain animals. In animals, toxins have similar defense potential and are also used to capture prey. Toxicity might, however, be less directly connected with environmental situations as in the case of fish and shellfish that become poisonous after feeding on toxic plants or algae.
Toxins are nowadays usually defined as poisonous substances produced by living organisms including bacteria, microalgae, plants or fungi. We will use here this definition and therefore restrict ourselves to natural substances affecting an animal.

1.3. Scope of the Review

The knowledge of toxins acting on the ligand gated ion channels (LGIC) is dispersed and not homogeneous. Some toxins were isolated and chemically characterized, but poorly studied on the LGIC afterwards. Others found very wide applications and are frequently used in research or even as therapeutic intervention. This in-homogeneity could be due to the fact that the study of toxins acting on LGIC is the intersection of two relatively separated fields: toxinology on one hand and the study of the LGIC on the other hand. Another explanation is that many of the toxins described below were discovered and characterized (and then forgotten?), before the diverse LGIC had been identified. We therefore decided to construct a list of toxins targeting the LGIC that would be as exhaustive as possible.
This compilation of toxins targeting the LGIC should be useful as toxins constitute a relatively unbiased—in term of chemical space covered—source of ligand structures that can be used: (i) as a source of inspiration for drug design, as much as hits identified from high-throughput screening experiments; (ii) in structure/activity relationship studies; (iii) in virtual screening studies. The structure of a representative member of each family of the ligand-gated ion channels has been very recently solved by X-ray crystallography making these studies timely.

2. Toxins Targeting the Ligand Gated Ion Channels

LGIC are allosteric proteins (for a recent review on the allosteric nature of nicotinic receptors, see [7]). Indeed, their functioning implies that they are in equilibrium between a few states, switching from the resting state to an active state with an open ion-channel, and eventually a desensitized state. In this framework, the ligands (agonists, antagonists and allosteric modulators) act by altering the equilibrium, i.e., they stabilize the state for which they have the highest affinity. The endogenous agonist binds, by definition, in the orthosteric binding site. The other ligands, notably toxins, bind either at the same site (agonists and competitive antagonists), or in other binding sites (allosteric modulators and non-competitive antagonists).
LGIC are oligomeric receptors made by the association of identical or homologous subunits [8]. The LGIC superfamilly can be subdivided into three families depending on the number of monomers composing an oligomer: the pentameric, tetrameric and trimeric LGIC.
The pentameric family encompasses the nicotinic acetylcholine receptors (nAChRs; α1-10, β1-4, γ, δ, ε), the Gamma-aminobutyric acid (GABA) receptors (α1-6, β1-3, γ1-3, δ, ε, θ, π, ρ1-3) receptors, the Serotonin (5-hydroxytryptamine, 5HT3) receptors (5-HT3A-E) and the Glycine receptors (α1-3, β) [9,10]. The endogenous agonist binding site lies at the interface between subunits (Figure 1). The location of alternative binding sites has been identified at homologous interfaces (e.g., benzodizepines for the GABA receptors) and in the transmembrane domain [11].
The tetrameric family of LGIC consists of glutamate receptors. This LGIC family contains the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors (GluA1-4), kainate receptors (GluK1-5) and N-methyl D-aspartate (NMDA) receptors (GluN1, GluN2A-D, GluN3A-B). The agonist binding site of tetrameric LGIC lies inside monomers (Figure 2). The agonists and alternative binding sites are known from biochemical and structural studies [12].
The trimeric family of LGIC is made by P2X receptors (P2X1-7). The knowledge of the binding site is much more restricted compared to that of pentameric and tetrameric LGIC: the binding site for ATP has been tentatively localized in a cavity at the interface between subunits (Figure 3).
Below are listed selected toxins, known to act on the various LGIC, that are important for historical or pharmacological reasons. This series of toxins is complemented by a list presented as an appendix (Section 5).
Figure 1. Structure of pentameric ligand-gated ion channels (LGIC). Muscle type nAChR is taken as an example. Top left: Topology of the receptor. Top right: Top view of the receptor. Bottom left: Side view of the receptor showing the extracellular, intracellular and transmembrane domains. Agonist binding sites are located at subunit interfaces in the extracellular side of the receptor. Bottom right: Longitudinal cross section of the receptor, showing the pore domain.
Figure 1. Structure of pentameric ligand-gated ion channels (LGIC). Muscle type nAChR is taken as an example. Top left: Topology of the receptor. Top right: Top view of the receptor. Bottom left: Side view of the receptor showing the extracellular, intracellular and transmembrane domains. Agonist binding sites are located at subunit interfaces in the extracellular side of the receptor. Bottom right: Longitudinal cross section of the receptor, showing the pore domain.
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2.1. Nicotinic Acetylcholine Receptors

Nicotinic receptors are arguably the most well-known LGIC to date. This is probably due to their very early discovery and the large number of toxins blocking them. Historically, the pharmaceutical knowledge of the cholinergic system has emerged with the “discovery” of curares by Spanish explorers in South America during the 16th century. Indeed, curares were used there by local tribes for hunting [1]. It was found during the 19th century that curares block the synaptic transmission at the level of the neuromuscular junction [13] therefore paralyzing the prey. Similar usage of curares have also been reported in Africa [14], and Malaysia [15]. Toxins had an invaluable contribution to the emergence of the notion of LGIC as nAChR where first defined as the “nicotine and curare receptive substance” [16].
Figure 2. Structure of tetrameric LGIC. NMDA receptor is taken as an example. Top left: Topology of the receptor. Top right: Top view of the receptor. Bottom left: Side view of the receptor showing the extracellular, intracellular and transmembrane domains. Agonist binding sites are located in juxta-membrane domains in the extracellular side of the receptor. Bottom right: Longitudinal cross section of the receptor, showing the pore domain.
Figure 2. Structure of tetrameric LGIC. NMDA receptor is taken as an example. Top left: Topology of the receptor. Top right: Top view of the receptor. Bottom left: Side view of the receptor showing the extracellular, intracellular and transmembrane domains. Agonist binding sites are located in juxta-membrane domains in the extracellular side of the receptor. Bottom right: Longitudinal cross section of the receptor, showing the pore domain.
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Another historically significant toxin targeting the nAChR is α-Bungarotoxin (reviewed in [17]). It was first used to isolate the nAChR [18,19]. The venoms of marine cone snails represent a rich combinatorial-like library of evolutionarily selected, neuropharmacologically active peptides called conotoxins (Figure 4, Table 1) that target a wide variety of receptors and ion-channels [20]. The subtype specific snake α-neurotoxins and cone snail α-conotoxins are still widely used to probe receptor structure and function in native tissues and recombinant systems [21].
Nicotine is a highly toxic alkaloid proposed to serve as an insecticide protecting Tobacco plants [22]. It is the prototypical agonist at nicotinic cholinergic receptors (Figure 5) in comparison to muscarinic receptors [23]. Tobacco extract was used as an insecticide for centuries [24], perhaps as early as 1690 [25]. The effect relies on the presence of nicotine and anabasine (see Section 5). Moreover, nicotine and anabasine were still in use in the early 20th century (see below). Nicotine is also important medically because it is thought to be responsible for tobacco addiction through the stimulation of α4β2 nAChR on dopaminergic neurons of the ventral tegmental area (VTA) [26].
Figure 3. A schematic view of trimeric LGIC (P2X receptor). Top left: Topology of the receptor. Top right: Top view of the receptor. Bottom left: Side view of the receptor showing the extracellular, intracellular and transmembrane domains. Agonist binding sites are presumably located at subunit interfaces in the extracellular side of the receptor. Bottom right: Longitudinal cross section of the receptor, showing the pore domain.
Figure 3. A schematic view of trimeric LGIC (P2X receptor). Top left: Topology of the receptor. Top right: Top view of the receptor. Bottom left: Side view of the receptor showing the extracellular, intracellular and transmembrane domains. Agonist binding sites are presumably located at subunit interfaces in the extracellular side of the receptor. Bottom right: Longitudinal cross section of the receptor, showing the pore domain.
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Figure 4. Representative protein toxins targeting the nicotinic acetylcholine receptors.
Figure 4. Representative protein toxins targeting the nicotinic acetylcholine receptors.
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Table 1. α-conotoxins acting on nAChRs.
Table 1. α-conotoxins acting on nAChRs.
NameConus specieTargetReferences
GI, GIA, GIIgeographusMuscle nAChR[27]
MImagusMuscle nAChR[28]
SI, SIA and SIIstriatusSelectivity for the distinct interfaces (α/γ or α/δ) of the muscle-type nAChR[28,29]
ImI, ImIIimperialisSelective for α7 nAChR but also effective on α3β4, α3β2[30]
BuIA bullatusHighest potency for α3- and α6−containing nAChRs[31]
CnIA, CnIB consorsMuscle nAChR[32]
Ac1.1a, Ac1.1bachatinusMuscle nAChR[33]
EIermineusSelective for muscle nAChR, also effective on α3β4, α4β2[34]
PnIB, (A10L)-PnIApennaceusSelective for α7, α3β4, α3β2 nAChR[35,36]
GICgeographusSelective for α3β2[37]
MII magnusSelective for α3β2, α3β2β3, α6* nAChR[38,39]
PIA purpurascensSelective for α6β2, α6β4, α6α3β2(β3), α6α3β4[40]
PIBpurpurascensMuscle nAChR[41]
GIDgeographusα7, α3β2, α4β2[42,43]
AuIA, AuIB and AuIC aulicusSelectively blocks α3β4 nAChRs[44]
EPI episcopatusSelective for α7, α3β2, α3β4[45,46]
AnIBanemoneα7, α3β2[47]
Vc1.1victoriaeα9, α3β4, α3(α5)β2[48,49]
ArIA, ArIBarenatusα7, α3β2α6α3β2β3[50]
PeIApergrandisα9α10,α6α3β2β3,α3β2[51]
OmIAomariaα7, α3β2[52]
TxIAtextileα3β2[53]
Lp1.1leopardusα3β2,α6α3β2[54]
SrIA, SrIBspuriousα4β2, muscle type nAChRs[55]
β-Erythroidine is isolated from the coral tree Erythrina crista-galli. It acts as a competitive antagonist of nicotinic receptors (it targets α4β4, α4β2 and α3β2* receptors and has weak affinity for the muscle type and α3β4) [56]. At high concentrations, they are noncompetitive blockers of possibly all nicotinic receptors subtypes [57,58,59]. Erysodine is a structurally related Erythrina Alkaloid acting on α4β2 and α3β2* nAChR. Both compounds are weak binders to α7 nAChR explaining that they are used to discriminate between different nAChR subtypes although they are relatively non-selective.
Figure 5. Representative alkaloids targeting the nicotinic acetylcholine receptors. Top: agonists, middle: competitive antagonists, bottom; non-competitive antagonists.
Figure 5. Representative alkaloids targeting the nicotinic acetylcholine receptors. Top: agonists, middle: competitive antagonists, bottom; non-competitive antagonists.
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Methyllycaconitine (MLA), is extracted from Delphinium species [60] and is a potent and highly selective α7 nAChR antagonist [61,62]. MLA is largely used for this property as a pharmacological tool in research [63]. MLA together with additional alkaloids in Delphinium species (nudicauline, 14-deacetylnudicauline, barbinine and deltaine) have also been found to act on nAChRs blocking the neuromuscular junction which may be related to the Delphinium species involvement in cattle poisoning [64,65].

2.2. GABA-A Receptors

The toxins of the GABA receptors are, as for the nAChR, of different categories (agonists, antagonists and allosteric modulators) as illustrated by the examples described below.
α-thujone is extracted from the wormwood Artemisia absinthium and is found in absinthe [66]. It is a negative allosteric modulator of GABA-A receptors (Figure 6) resulting in convulsant activity [67]. α-thujone also antagonizes 5HT3 receptors [68].
Figure 6. Representative toxins targeting the GABA receptors.
Figure 6. Representative toxins targeting the GABA receptors.
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Bicuculline, isolated from Dicentra cucullaria, is a competitive antagonist of GABA-A receptors causing convulsions [66].
Muscimol is an agonist extracted from Amanita muscaria partly responsible for the toxic effect of the mushroom [66].
Picrotoxin is a non-competitive antagonists isolated from Menispermaceae. Binding modes for picrotoxin have been proposed in the ion channel [69,70,71].

2.3. Glycine Receptors

Strychnine is found in the seeds of the Strychnine tree (Strychnos nux-vomica). Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion. It is used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine participates in the pharmacological differentiation of receptors responsive to glycine. Indeed, some NMDA receptors are also activated by glycine but are strychnine insensitive [72].

2.4. Serotonin Receptors

The serotonin receptors have very few known toxins: Conotoxin GVIIA (σ-conotoxin; a large 41 amino-acids conotoxin [73]) and d-tubocurarine.
d-Tubocurarine is a mono-quaternary alkaloid obtained from the bark and stems of Chondrodendron tomentosum. d-Tubocurarine blocks nAChRs at the neuromuscular junction but also acts on serotonin receptors [74]. d-Tubocurarine is the archetypal curare. As neuromuscular blockers, curares can be used as skeletal muscle relaxants and were indeed introduced in anesthesia in 1942 [75]. Curares are active only by injection. They are harmless if taken orally because curare compounds are too large and too highly charged to pass through the lining of the digestive tract to be absorbed into the blood. This explains how they can be used to kill prey that will be later ingested.

2.5. NMDA Receptors

Ageltoxin (agatoxin) are arylamine toxins (the α-agatoxins) found in the venom of the spider Agelenopsis aperta. They paralyze insects by blocking glutamatergic neuromuscular transmission [76]. Ageltoxins are thought to be non-competitive channel blockers specific for NMDA receptors [76,77].
Conantokins are found in the venom from Conus fish hunting snails [78]. The conantokins (G, L, R and T) form a class of peptides that inhibit competitively NMDA receptors [79,80]. Interestingly conantokins possess a large number of γ-carboxyglutamic acid residues (Figure 7) [81]. One of the γ−carboxyglutamic acid residues is thought to participate in the selectivity of conantokin G [82].

2.6. AMPA Receptors

Quisqualic acid is isolated from the seeds of Quisqualis indica. Quisqualic acid is an agonist at AMPA receptors [83]. Quisqualate used to be the prototypical ligand of AMPA receptors, which were therefore called quisqualate receptors. However, this name has been abandoned as quisqualate also acts at metabotropic glutamate receptors [83].

2.7. Kainate Receptors

Kainic acid was first isolated from the red alga Digenia simplex, where it might play a defense role, [84] and is also found in other algae [85]. Kainic acid is the prototypical agonist defining the Kainate subtype of glutamate receptors. The toxin is associated with human poisoning through the consumption of mussels that eat the algae.

2.8. P2X Receptors

Purotoxin are P2X receptors modulators which were isolated from the venom of the wolf spider Geolycosa sp [86]. Later, purotoxin has been isolated and shown to be a non-competitive antagonist of the P2X3 receptors [87]. It was found to be a close homologue to other spider toxins of unknown function and a more distant homologue to toxins known to bind to other receptors [87]. However, none of the receptors tested, besides P2X3, were sensitive to purotoxin, which makes it to date the only toxin specific of P2X receptors [87].
Figure 7. Representative toxins targeting the glutamate receptors. Top: NMDA receptors; Middle: AMPA receptors; Bottom: Kainate receptors.
Figure 7. Representative toxins targeting the glutamate receptors. Top: NMDA receptors; Middle: AMPA receptors; Bottom: Kainate receptors.
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3. Current and Proposed Medical Use of Toxins Targeting the LGIC

Neurotoxins are great sources of medicine or cosmetic products [4]. In addition to their usage as analgesics [79], they are now evaluated as potential treatment for many pathologies [4,6,88]. The toxins presented below are those that are used in clinic or that entered clinical trials (clinical trials were monitored using the website clinicaltrial.org). However, for some LGICs, no toxin has reached clinical trials. Therefore, this section is also complemented with information from patents and recent preclinical data.
An important characteristic of all the toxins presented below is that they are not used as alternative strategies because of toxic properties [89]. Instead, the toxins targeting LGIC are used for their modulating activity.

3.1. nAChR

The nAChR has the largest number of known toxins (Sections 2 and 5). It is probably not surprising that nAChR also has the largest number of toxins used medically. Interestingly, both agonists and antagonists are used differently to what is observed for most of the other LGIC.

3.1.1. Agonists

nAChR agonists are considered for their central action and, beyond treatment of tobacco addiction, the main targeted effect is cognition stimulation.
Three agonists are used to treat tobacco dependence: Cytisine (in eastern and central Europe) [90], Lobeline [91] and Nicotine.
nAChR agonists are also considered in the treatment of neurological disorders. Nicotine is evaluated for Parkinson’s disease (phase II), schizophrenia (phase IV), sarcoidosis (phase IV) and pain (phase IV). Lobeline is evaluated for therapeutic intervention in Attention Deficit Hyperactivity Disorder (phase II). Epibatidine has been evaluated for the treatment of pain in phase II clinical trials (as ABT-594) and later abandoned because of adverse effects [4]. GTS21 (derived from anabaseine) is evaluated (phase II) for therapeutic intervention against schizophrenia [92].

3.1.2. Competitive Antagonists

Curares derived from d-tubocurarine are widely used for local anesthesia as myo-relaxant. The curare pancuronium is also used for enforcing the death penalty. The reader is referred to the review of Norman Bisset [1] for a historical perspective on the use of curares.
Cobratoxin is used in traditional medicine in China [93] and India. Cobratoxin use has also been proposed for the treatment of small and non-small cell lung cancer by blocking the α7 nAChRs [94,95,96,97,98]. Cobratoxin has also been proposed for the treatment of pain [99] and Multiple sclerosis [100]. In terms of the latter pathology, a chemically attenuated version of cobratoxin [101], also known as receptin or RPI-78M, is under investigation in a phase II clinical trial.
Conotoxins hold a significant therapeutic potential that has been reviewed recently [3,4]. α-conotoxin Vc1.1, which targets α9α10 νAChRs, has been tested in a phase II clinical trial (as ACV1) but the development was later discontinued. It should be noted that α-conotoxin Vc1.1 has been proposed to target also the N-type calcium channel [102,103,104]. Muscle-selective α-conotoxins (e.g., α-GI), could represent an alternative to the use of small molecule curare-mimetic muscle relaxants, which are used during surgery, but have slower than ideal recovery period [4,105].

3.1.3. Non-Competitive Antagonists

Strychnine used to be prescribed for the treatment of myasthenia until 1930 [106]. “Myasthenia”, however, encompass very diverse pathologies that were not discriminated before the 20th century [107]: (i) Myasthenia gravis is an autoimmune disease [107]; (ii) congenital myasthenia syndromes are associated with genetic alterations, some of them increasing or decreasing nAChR response to ACh [108]. Using an antagonist like strychnine cannot be beneficial to treat cases of reduced cholinergic signaling. Such a treatment could only be beneficial for the cases displaying an increased activity of the nAChR, i.e., the slow channel congenital myasthenia. Interestingly, quinidine, which acts as a non competitive antagonist—strychnine has a similar effect on muscle nAChR [109]—is used nowadays to treat patients with slow-channel congenital myasthenia.
Mecamylamine is a drug introduced in the 1950s as an anti-hypertensive agent and is now (as TC5214) under clinical trials (phase III) for the treatment of Major Depressive Disorder.

3.2. Other Pentameric Ligand Gated Ion Channels

None of the toxins targeting the other pentameric LGIC (GABA, Glycine, Serotonin) have been used in medical practice. Furthermore, none of the toxins targeting these receptors has entered clinical trials.
For GABA receptors, a patent proposes the use of either the agonist muscimol or the antagonist bicuculine for the treatment of myopia. Numerous, synthetic compounds targeting the GABA receptors are on the market, the most significant being barbiturates and benzodiazepines. These compounds act by increasing the mean open time of the ion channel.
Among synthetic compounds, anesthetics (e.g., propofol) potentiate Glycine receptors. However, propofol also acts on GABA receptors. Currently, no drug targets specifically Glycine receptors [110]. The amino-acid taurine, found in energizing sodas is an inhibitor of the Glycine receptor [111].
Synthetic antagonists targeting the Serotonin receptors are used as antiemitic drugs [112]. Similarly, natural compounds targeting the Serotonin receptors have antiemitic properties, e.g., ginger extracts and delta-9-tetrahydrocannabinol from Cannabis sativa.

3.3. NMDA Receptors

Toxins targeting the NMDA receptors (Figure 7, top) have neither been used medically nor tested clinically. Synthetic compounds targeting the NMDA receptors in clinical use are mainly channel blockers (Ketamine, Memantine, Amantadine) but also antagonists (Felbamate) [113]. Partial agonists have also been tested clinically (GLYX-13 and Acomposate).
Conantokins G and T have been noticed to display antinociceptive [114,115] and anti-epileptic properties [4,116]. Some conantokins demonstrate receptors subunit selectivity, which makes them attractive drug candidates [117].
Domoic acid containing algae are used as vermifugal agents in Japanese traditional medicine [118].

3.4. AMPA Receptors

Toxins targeting the AMPA receptors (Figure 7, middle) have neither been used medically nor tested clinically. The only drug on the market targeting AMPA receptors is the potentiator Aniracetam (in Italy and Greece). Drugs targeting the AMPA receptors that entered clinical trials were either antagonists (e.g., E2007/perampanel advanced in phase III) or positive allosteric modulators.

3.5. Kainate Receptors

Kainic acid is used in Chinese and Japanese traditional medicines as an anthelmintic to treat ascarialis [118]. Kainic acid is the only toxin targeting the kainate receptors (Figure 7, bottom) used as a treatment, and none have been tested clinically.

3.6. P2X

No drug targeting P2X receptors is on the market yet [119] and only very few clinical trials have been performed on that target (CE-224535 and GSK-1482160, which are not toxins). This observation can probably be explained by the very recent discovery of this family of LGIC. However, P2X receptors are attracting a lot of interest from pharmaceutical companies as shown by the significant number of patents filled recently [120]. All of the compounds proposed to target P2X receptors are antagonists. In agreement with this observation, among toxins targeting the P2X receptors (Figure 8), Purotoxin has been proposed for the treatment of pain based on the observation of antinociceptive activity in animal testing [87].
Figure 8. Representative toxins targeting P2X receptors.
Figure 8. Representative toxins targeting P2X receptors.
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4. Conclusion

One significant observation made during the preparation of this review is that the number of toxins acting on each family of LGIC is highly variable, ranging from a large number acting on nAChR to little acting on others like P2X receptors (see Sections 2 and 5). Two biological explanations can be proposed:
Although LGIC are mainly considered for their role at synapses they are also found in organisms that do not have any synapse [121]. Indeed, homologous proteins have been found in prokaryotes for pentameric [122,123] and tetrameric [124] LGIC but are still to be found for P2X receptors. It can therefore be proposed that P2X receptors appeared more recently in evolution and that the early emergence of pentameric and tetrameric LGIC could have allowed more time for toxin co-evolution.
The physiological roles of the diverse LGIC could also play a role in the imbalance in the number of toxins targeting the LGICs. Indeed, nAChRs, which are largely targeted by toxins, have a prominent role at the neuromuscular junction and, as mentioned above, numerous toxins target that function. Glutamate receptors are also involved in the neuromuscular transduction in invertebrates [125]. In comparison, the role of P2X receptors at the neuromuscular junction is limited in that it does not participate directly in the transmission, but in the neuro-muscular junction development and regeneration [126], and should therefore be a less critical target for prey capture.
In addition to these biological explanations, the asymmetry in the knowledge of toxins targeting LGIC could also be due to the lack of research on the latter identified P2X receptors compared to the first identified nicotinic receptors. Indeed, the targeted receptor is not necessarily obvious from the symptoms and specificity of action may come from other reasons than pharmacological ones, i.e., many toxins can affect receptors present in the CNS whereas they do not reach them physiologically. The known interactions therefore largely depend on specific studies on the effect of toxins on LGIC that are themselves asymmetric.
Given the therapeutic potential of toxins, this observation makes the quest for new toxins targeting P2X receptors an attractive area of research.

Appendix: List of Toxins Targeting the LGIC

1. Nicotinic Acetylcholine Receptors

1.1. Peptides and Proteins

1.1.1. Conotoxins

α-conotoxins (Table 1) constitutes the largest group of conotoxins that target muscle nAChRs and/or specific subtypes of neuronal nAChRs in mammals [29]. α-conotoxins can distinguish amongst different subunit arrangements and therefore represent valuable pharmacological tools for research and hold therapeutic promises [127].
Table 1. α-conotoxins acting on nAChRs.
Table 1. α-conotoxins acting on nAChRs.
NameConus SpecieTargetReferences
GI, GIA, GIIgeographusMuscle nAChR [27]
MImagusMuscle nAChR [28]
SI, SIA and SIIstriatusSelectivity for the distinct interfaces (α/γ or α/δ) of the muscle-type nAChR [28,29]
ImI, ImIIimperialisSelective for α7 nAChR but also effective on α3β4, α3β2 [30]
BuIAbullatusHighest potency for α3- and α6−containing nAChRs [31]
CnIA, CnIB consorsMuscle nAChR [32]
Ac1.1a, Ac1.1bachatinusMuscle nAChR [33]
EIermineusSelective for muscle nAChR, also effective on α3β4, α4β2 [34]
PnIB, (A10L)-PnIApennaceusSelective for α7, α3β4, α3β2 nAChR [35,36]
GICgeographusSelective for α3β2 [37]
MII magnusSelective for α3β2, α3β2β3, α6∗ nAChR [38,39]
PIA purpurascensSelective for α6β2, α6β4, α6α3β2(β3), α6α3β4 [40]
PIBpurpurascensMuscle nAChR [41]
GIDgeographusα7, α3β2, α4β2 [42,43]
AuIA, AuIB and AuICaulicusSelectively blocks α3β4 nAChRs [44]
EPI episcopatusSelective for α7, α3β2, α3β4 [45,46]
AnIBanemoneα7, α3β2 [47]
Vc1.1victoriaeα9, α3β4, α3(α5)β2 [48,49]
ArIA, ArIBarenatusα7, α3β2, α6α3β2β3 [50]
PeIApergrandisα9α10,α6α3β2β3,α3β2 [51]
OmIAomariaα7, α3β2 [52]
TxIA textileα3β2 [53]
Lp1.1 leopardusα3β2,α6α3β2 [54]
SrIA, SrIBspuriousα4β2, muscle type nAChRs [55]
α-conotoxins selectively antagonize the foetal subtype of the mammalian neuromuscular nAChR. A few have been identified: αAS OIVA and OIVB (from C. obscures), αAS PeIVA and αAS PeIVB (from C. pergrandis), αA PIVA (from C. purpurascens), αA EIVA and αA EIVB (from C. ermineus), αC PrXA (C. parius), or αS RVIIIA (C. radiates).
Non-α-conotoxins act on muscle-type nAChRs. ψ-conotoxin PIIIE (from C. purpurascens) has a structure similar to that of the voltage-gated Na+ channel-blocking μ-conotoxins and acts as a non-competitive antagonist (perhaps a pore blocker) of the muscle-type nAChR [44]. ψ-conotoxin PIIIF has also been identified in C. purpurascens and ψ-PrIIIE in C. parius.

1.1.2. Snake Neurotoxins

Snake neurotoxins have the same neuromuscular blocking effects than the plant alkaloid (+)-tubocurarine, but with approximately 15–20-fold greater affinity and poor reversibility of action. They are referred to as curaremimetic neurotoxins or postsynaptic neurotoxins (Table 2). Snake venom α-neurotoxins are polypeptides of 60–74 amino acid residues with 4-5 disulfide bridges, divided as short- (60–62 amino acids, 4 disulphide bridges) and long-chains (66–75 amino acids, 5 disulphide bridges).
Table 2. Snake neurotoxins acting on nAChRs.
Table 2. Snake neurotoxins acting on nAChRs.
NameSourceTargetStructural GroupReferences
α-BungarotoxinBungarus multicinctusMuscle, α7.Long-chain α-neurotoxin [128,129]
NmmINaja mossambica mossambicaMuscleshort-chain α-neurotoxin [130]
κ−bungarotoxinsBungarus genusα3β2 and other β2-containing nAChRs.long-chain neurotoxin [131]
α-cobratoxinNaja genus (e.g., Naja kaouthia)Muscle, α7long-chain α-neurotoxins [132]
Erabutoxin-a.Laticauda semifasciataMuscleShort-chain α-toxin
erabutoxin-bLaticauda semifasciataMuscleshort-chain neurotoxin [133]
Toxin-αNaja nigricollisMuscleshort-chain α-neurotoxin
The human protein Lynx1 has been proposed to be evolutionary related to snake venom toxins [134,135]. It binds tightly to nAChRs and inhibits their activation. It has been shown that Lynx1 both decreases nAChR sensitivity to ligands and increases desensitization.
Denmotoxin is present in the venom from the Colubrid snake Boiga dendrophila (Mangrove Catsnake). It displays remarkable species specificity, being able to interact irreversibly and with high affinity with chick muscle nAChR, but only with low affinity with mouse nAChR [136].
Waglerins are polypeptide isolated from the venom of South Asian snake Tropidolaemus wagleri consisting of 22–24 amino acids and containing one disulfide bridge. These toxins interact with high affinity with muscle-type nAChR [137].
Weak neurotoxins form the group of three fingered toxins consisting of 62-68 amino acid residues with five disulfide bridges characterized by low toxicity. Toxins of this type were later referred to as melanoleuca or miscellaneous-type or non-conventional toxins (Table 3). They bind to neuronal as well as Torpedo nAChRs, although with low (micromolar) affinities [138].
Acanthophin is found in death adder venoms; they are rich in a diversity of ‘short-chain’ and ‘long-chain’ postsynaptic neurotoxins that bind to nAChR in skeletal muscle and produce facial and bulbar paralysis.

1.1.3. Natural Toxic Peptides from Other Species

Philanthotoxin is found in the venom from the Egyptian digger wasp Philanthus triangulum and acts both as competitive and noncompetitive antagonist [148].
Huwentoxin is a neurotoxic peptide purified from the venom of the Chinese bird spider Selenocosmia huwena. This family consists of several types. Huwentoxin-1 is a lethal neurotoxin that binds to the nAChR and blocks neuromuscular transmission. Huwentoxin-2 blocks neuromuscular transmission and acts cooperatively to potentiate the activity of Huwentoxin-I [149,150].
Table 3. Weak neurotoxins acting on nAChR.
Table 3. Weak neurotoxins acting on nAChR.
NameOriginTargetOther specificationsReferences
CandoxinBungarus candidusα7 and muscle. [ 139]
CM-11, CM-2Naja haje haje (Egyptian cobra)Muscle [ 140]
CM10, CM12, CM-13b, CM-14Naja haje annuliferaNeuromuscular Junction [ 141]
Cm-9aN. kaouthia
S4C11 N. melanoleucaI. neurotoxin Homologue [ 142]
S5C1, S5C10Dendroaspis jamesoni kaimosae (Eastern Jameson's mamba)Muscle [ 143]
S6C4Dendroaspis jamesoni Kaimosae (jameson’s mamba) 67% sequence identity with Bucandin.
γ-bungarotoxinBungarus multicinctuspost synaptic action [ 144]
WTX Naja kaouthiaα7 and muscle. [ 138]
Wntx-5 Naja sputatrixTorpedo α1βγδ, chick α7 [ 145]
NNA2 the Taiwan cobra (N. n. atra)Musclelong-neurotoxin homologue [ 146]
LSIIILaticauda Semifasciataneuromuscular blockade [ 147]

1.2. Alkaloids

Cytisine from the golden chain tree is a natural agonist of nicotinic α4β2/α3β4*/α7 receptors. Other Cytisine-like analogs are caulophylline and tinctorine [151].
Comparing Nicotine with cytisine and caulophylline allowed drawing attention on the effect of pKa on activity [152]. This observation, in turn, paved the way for the proposal that alkaloids bind through a cation/pi interaction with aromatic residues present in the nAChR orthosteric binding site.
Anatoxin-a is a natural agonist produced by diverse cyanobacteria throughout the world [153]. Anatoxin-a is a cyanotoxin considered as an environmental issue as it is found in water bodies and promotes animal deaths [154]. In addition, given that intoxication due to anatoxin-a is possible from drinking water it has been considered that it could be used as biological weapon. For all those reasons numerous detection methods have been developed [155]. Anatoxin-a has nanomolar affinities for α4β2, α3β4* and α7nAChR. An analog is homoanatoxin.
Epibatidine is a potent nicotinic agonist from Dendrobatid frog (Epipedobates tricolor) with antinociceptive properties [156]. Epibatidine has selectivity for α4β2 > α3β4 > α7 > α1β1γδ.
Other nicotinic alkaloids from Epipedobates tricolor are N-methylepibatidine, Epiquinamide and nicotine. Epiquinamide is selective for nicotinic receptors containing the β2-subunit.
Anabasine is found in various natural sources like plant Nicotiana glauca, ant Aphaenogaster fulva, marine worm Paranemertes Peregrina. Anabaseine is an agoinst for α4β2 and α7 nAChR. Anabaseine which is a potent agonist on muscle and neuronal α-Bungarotoxin-sensitive nicotinic receptors [157], is found in tobacco and is also present in small amounts in tobacco smoke. Anabasine has been used as an insecticide.
Histrionicotoxin is a toxin isolated from skin secretions of a Colombian frog, Dendrobates histrionicus. It is a potent non-competitive antagonist of nAChR. More than 100 toxins have been identified from the skin secretions of members of the Dendrobatidae family of frogs, especially Dendrobates and Phyllobates. Members of the genus Dendrobates (of which there are at least 44 known species) are also known as "poison dart" or "poison arrow" frogs [158].
Ferruginine is a rather weak agonist of neuronal type nAChR from plant Darlingia ferruginea, other analogs include darlingine [159].
Carbamylcholine like acetylcholine activates both nicotinic and muscarinic receptors. The affinity for nicotinic receptors is in the order of α4β2 > α3β4∗ > α7.
Toxiferines are isolated from Strychnos species. C-toxiferine I (also refered to as toxiferine) is a quaternary alkaloids and, like tubocurarin, is a curare that acts as a competitive antagonist for nicotinic receptors, but is relatively nonselective. They were first found very potent to block the neuromuscular junction [160]. Toxiferine I, among neuronal type nAchR tested was found to bind mainly on α7 subtype [161]. Toxiferines were first used in anesthesia but were abandoned later because their effect was prolonged over too long periods [162].
Neosurugatoxin, a complex alkaloid glycoside isolated from a mollusk, Babylonia japonica [163], is a potent nicotinic competitive antagonist which blocks both muscle and neuronal nAChR [3,164,165,166].
Ibogaine is found principally in the west african Tabernanthe iboga were it is used in ceremonies of the Bwiti religion [167]. It was used for its anti-addictive properties but was later banned for being addictive [167]. It is a noncompetitive blocker of nicotinic receptors [168], and also interacts with other proteins including NMDA receptors [167].
Strychnine is a non-competitive antagonist at α4β2 receptors but acts as a competitive antagonist at α7 receptors [169].
Coaine is found in the plant source Erythroxylon Coca and is is a noncompetitive blocker in particular for α4β receptors. The quaternary methiodide of cocaine represents another α7-selective agonist [170].
Sparteine, a lupin alkaloid extracted from Lupinus luteus, has been found to be an antagonist for α3β4 receptors. Lupin alkaloids are found in wide variety of plants around the world and are generally toxic [171,172].
Parazoanthoxanthin A is a fluorescent pigment of the group of zoanthoxanthins. It has been shown that Parazoanthoxanthin A demonstrates a dual action on Torpedo nAChR; both as a pore blocker and a competitive antagonist [173].

1.3. Others

Lophotoxin from various Pseudopterogorgia species, gorgonian soft corals, is a potent and irreversible antagonist for neuromuscular-type nicotine receptors [174,175,176,177]. Lophotoxin appears selective towards α4β2 and α1β1γδ nicotinic receptors [178]. It was found to react with Trp 190 in the α-subunit [179]. Its analogue Bipinnatin B has similar properties [180].
Luffarins (K, L and R) as well as Comentins (A, B and C) are non-specific antagonists extracted from Australian soft corals [3].

2. GABA-A Receptors

Cicutoxin from the leaves of Cicuta virosa causes convulsion and respiratory paralysis [181].
Cunaniol from the leaves of Clibadium sylvestre a GABAA antagonist is a potent convulsant [181].
Ethanol is apositive modulator of GABA receptors [181].

3. Glycine Receptors

Brucine is a plant alkaloid found in several species, most notably the Strychnine tree (Strychnos nux-vomica L.). Brucine is structural related to strychnine.
Tutin is a plant toxin found in the tutu plant (genus Coriaria). It has powerful convulsant effects.

4. Serotonin Receptors

The serotonin receptors have very few known toxins: Conotoxin GVIIA (σ-conotoxin; a large 41 amino-acids conotoxin [73]) and d-tubocurarine (see nAChRs).

5. NMDA

Ibogaine see nAChR.
Ibotenic acid was first isolated from the fungus Amanita ibotengutake [182,183]. The fungus Amanita muscaria (fly agaric) got its name from its poisonous actions on flies [184].
Kaitocephalin was isolated from the fungus Eupenicillium shearii as a glutamate receptor antagonist, which protected from kainate toxicity [185].
Kaitocephalin was latter found to be an antagonist of NMDA and AMPA receptors and also a weak antagonist of the KA-type receptor GluK2 [186].
Phoneutriatoxin is isolated from the spider Phoneutria nigriventer. It was found to have effect on Glutamate uptake [187,188] and to be specific of NMDA receptors [189].

6. AMPA

DABA (2,4-diaminobutyric acid) and BOAA (beta-N-oxalylamino-L-alanine) are found in the seeds of the flat pea Lathyrus sylvestris. Both DABA and BOAA are excitatory neurotoxins acting on the AMPA-type receptors [184].
Philanthotoxins (alpha, beta, gamma, delta) were first isolated from the wasp Philanthus triangulum. δ−philanthotoxin blocks glutamate receptors [190], both AMPA [191] and kainate [192].
Philanthotoxin forms the class of polyamine toxins with argiotoxin, Joro spider toxin and agatoxin. Polyamine toxins are non-competitive antagonist binding probably at the ion channel [193].
Argiotoxins were first isolated from the spider Argiope lobata [194]. Argiotoxin is an inhibitor of NMDA and kainate receptors [195].
Joro spider toxin was isolated from the Joro spider Nephilia clavata [196]. Joro spider toxin shows analgesic properties [197].
Willardiine was first isolated from seeds of Acacia willardiana [198] and latter from Acacia lemmoni, Acacia millefolia, and Mimosa asperata [198]. Willardiine acts as an agonist on the AMPA and kainate receptors [199].

7. Kainate Receptors

Kainic acid is the first membre of the Kainoids familly of molecules that also encompass notably Domoic acid and acromelic acid. Acromelic acids (A, B and C) are found in the poisonous mushroom Clitocybe acromelalga [200]. Domoic acid was originally isolated from the red alga Chondria armata and was found in the genus Pseudonitzschia and the species Nitzschia navis-varingica. Domoic acid is associated with Amnesic shellfish poissoning [85]. Domoic acid also activates AMPA-type receptors [201].
Dysiserbaine is a neuroexcitotoxic amino acid isolated from the Micronesian marine sponge Dysidea herbacea. Dysiserbaine is another kainate-receptors specific molecule that is structurally unrelated to Kainoids [85].
Concanavalin A is a plant lectin isolated from jack bean (Canavalia ensiformis) [202]. It was found to be a positive allosteric modulator [203].

8. P2X Receptors

α-Conotoxin GVIA has first been known to be a N-type calcium channel blocker [204]. It was latter shown to be also a potent inhibitor of P2X3 and P2X2/X3 receptors [205]. The observation that they move dose-response curves to higher ATP concentrations without affecting gating kinetics suggests that it is a non-competitive inhibitor [205].
α-Hemolysin promotes the formation of pore leading to hemolysis [206]. As P2X7 are known to open large pores their involvement has been tested. It was shown that α-Hemolysin effect involves P2X1 and P2X7 [206]. It might be speculated that this cytotoxic activity is related to cell death routes involving P2X receptors. In a related manner, Porphyromonas gingivalis toxicity requires the secretion of an ATP-consumption enzyme to prevent apoptosis [207].
Endotoxin. Lipopolysaccharides have been shown to increase levels of P2X4/P2X7 expression in mouse hypocampus [208]. It was suggested that P2X receptors might have a role in IL-1 release [208] in addition to Toll-like receptor 4 [209]. Indirect effect of LPS could also be through modification of ATP levels [210].
Maitotoxin was first proposed to act on P2X7 receptors because pores opened by maitotoxin could not be differenciated from those induced by the agonist Bz-ATP [211]. Thanks to variations in buffers and antagonists it was latter found that the effect is complementary [212].

References

  1. Bisset, N.G. One man's poison, another man's medicine? J. Ethnopharmacol. 1991, 32, 71–81. [Google Scholar] [CrossRef] [PubMed]
  2. Rainsford, K.D. Ibuprofen: Pharmacology, efficacy and safety. Inflammopharmacology 2009, 17, 275–342. [Google Scholar]
  3. Livett, B.G.; Sandall, D.W.; Keays, D.; Down, J.; Gayler, K.R.; Satkunanathan, N.; Khalil, Z. Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor. Toxicon 2006, 48, 810–829. [Google Scholar]
  4. Lewis, R.J.; Garcia, M.L. Therapeutic potential of venom peptides. Nat. Rev. Drug. Discov. 2003, 2, 790–802. [Google Scholar]
  5. Brieger, L. Zur Kenntniss der Aetiologie des Wundstarrkrampfes nebst Bemerkungen über das Choleraroth. Dtsch. Med. Wochenschr 1887, 13, 303–305. [Google Scholar]
  6. Pastan, I.; Chaudhary, V.; FitzGerald, D.J. Recombinant toxins as novel therapeutic agents. Annu. Rev. Biochem. 1992, 61, 331–354. [Google Scholar]
  7. Changeux, J.P.; Taly, A. Nicotinic receptors, allosteric proteins and medicine. Trends. Mol. Med. 2008, 14, 93–102. [Google Scholar]
  8. Collingridge, G.L.; Olsen, R.W.; Peters, J.; Spedding, M. A nomenclature for ligand-gated ion channels. Neuropharmacology 2009, 56, 2–5. [Google Scholar]
  9. Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 2002, 3, 102–114. [Google Scholar]
  10. Le Novere, N.; Changeux, J.P. LGICdb: The ligand-gated ion channel database. Nucleic. Acids. Res. 2001, 29, 294–295. [Google Scholar]
  11. Baenziger, J.E.; Corringer, P.J. 3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels. Neuropharmacology 2011, 60, 116–125. [Google Scholar]
  12. Traynelis, S.F.; Wollmuth, L.P.; McBain, C.J.; Menniti, F.S.; Vance, K.M.; Ogden, K.K.; Hansen, K.B.; Yuan, H.; Myers, S.J.; Dingledine, R. Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol. Rev. 2010, 62, 405–496. [Google Scholar] [CrossRef] [PubMed]
  13. Bernard, C. Leçons sur les effets des substances toxiques et médicamenteuses; Collège de France: Paris, France, 1857. [Google Scholar]
  14. Angenot, L.; Denoel, A.; Goffart, M. Curare-like effect of African Strychnos: Strychnos usambarensis Gilg du Rwanda. J. Pharm. Belg. 1970, 25, 73–77. [Google Scholar]
  15. Bisset, N.G. War and hunting poisons of the New World. Part 1. Notes on the early history of curare. J. Ethnopharmacol. 1992, 36, 1–26. [Google Scholar] [CrossRef] [PubMed]
  16. Langley, J.N. On nerve ending and on special excitable substances in cells. Proc. Roy. Soc. Ser. B 1906, 78, 170–194. [Google Scholar]
  17. Changeux, J.-P.; Edelstein, S.J. Nicotinic Acetylcholine Receptors: From Molecular Biology to Cognition; Odile Jacob: New York, NY, USA, 2005; p. 284. [Google Scholar]
  18. Changeux, J.P.; Kasai, M.; Huchet, M.; Meunier, J.C. Extraction from electric tissue of gymnotus of a protein presenting several typical properties characteristic of the physiological receptor of acetylcholine. C. R. Acad. Sci. Hebd. Seances. Acad. Sci. D 1970, 270, 2864–2867. [Google Scholar]
  19. Changeux, J.P.; Podleski, T.R.; Wofsy, L. Affinity labeling of the acetylcholine-receptor. Proc. Natl. Acad. Sci. USA 1967, 58, 2063–2070. [Google Scholar]
  20. Favreau, P.; Le Gall, F.; Benoit, E.; Molgo, J. A review on conotoxins targeting ion channels and acetylcholine receptors of the vertebrate neuromuscular junction. Acta. Physiol. Pharmacol. Ther. Latinoam. 1999, 49, 257–267. [Google Scholar]
  21. Vogel, Z.; Sytkowski, A.J.; Nirenberg, M.W. Acetylcholine receptors of muscle grown in vitro. Proc. Natl. Acad. Sci. USA 1972, 69, 3180–3184. [Google Scholar] [CrossRef]
  22. Morris, C.E.; Harrison, J.B. Central nervous system features of a nicotine-resistant insect, the tobacco hornworm Manduca sexta. Tissue Cell 1984, 16, 601–612. [Google Scholar]
  23. Dale, H.H. The action of certain esters and ethers of choline, and their relation to muscarine. J. Pharmacol. Exp. Ther 1914, 6, 147–190. [Google Scholar]
  24. Tomizawa, M.; Casida, J.E. Molecular recognition of neonicotinoid insecticides: The determinants of life or death. Acc. Chem. Res 2009, 42, 260–269. [Google Scholar]
  25. Matolcsy, G.; Nádasy, M.; Andriska, V. Pesticide Chemistry; Elsevier: Amsterdam, The Netherlands, 1988; p. 808. [Google Scholar]
  26. Maskos, U.; Molles, B.E.; Pons, S.; Besson, M.; Guiard, B.P.; Guilloux, J.P.; Evrard, A.; Cazala, P.; Cormier, A.; Mameli-Engvall, M.; Dufour, N.; Cloez-Tayarani, I.; Bemelmans, A.P.; Mallet, J.; Gardier, A.M.; David, V.; Faure, P.; Granon, S.; Changeux, J.P. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 2005, 436, 103–107. [Google Scholar]
  27. Marshall, I.G.; Harvey, A.L. Selective neuromuscular blocking properties of alpha-conotoxins in vivo. Toxicon 1990, 28, 231–234. [Google Scholar] [CrossRef] [PubMed]
  28. Arias, H.R.; Blanton, M.P. Alpha-conotoxins. Int. J. Biochem. Cell Biol. 2000, 32, 1017–1028. [Google Scholar]
  29. McIntosh, J.M.; Santos, A.D.; Olivera, B.M. Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes. Annu. Rev. Biochem. 1999, 68, 59–88. [Google Scholar]
  30. Ellison, M.; McIntosh, J.M.; Olivera, B.M. Alpha-conotoxins ImI and ImII. Similar alpha. 7 nicotinic receptor antagonists act at different sites. J. Biol. Chem. 2003, 278, 757–764. [Google Scholar] [PubMed]
  31. Azam, L.; Dowell, C.; Watkins, M.; Stitzel, J.A.; Olivera, B.M.; McIntosh, J.M. Alpha-conotoxin BuIA, a novel peptide from Conus bullatus, distinguishes among neuronal nicotinic acetylcholine receptors. J. Biol. Chem. 2005, 280, 80–87. [Google Scholar] [PubMed]
  32. Favreau, P.; Krimm, I.; Le Gall, F.; Bobenrieth, M.J.; Lamthanh, H.; Bouet, F.; Servent, D.; Molgo, J.; Menez, A.; Letourneux, Y.; Lancelin, J.M. Biochemical characterization and nuclear magnetic resonance structure of novel alpha-conotoxins isolated from the venom of Conus consors. Biochemistry 1999, 38, 6317–6326. [Google Scholar]
  33. Liu, L.; Chew, G.; Hawrot, E.; Chi, C.; Wang, C. Two potent alpha3/5 conotoxins from piscivorous Conus achatinus. Acta Biochim. Biophys. Sin (Shanghai) 2007, 39, 438–444. [Google Scholar] [CrossRef] [PubMed]
  34. Martinez, J.S.; Olivera, B.M.; Gray, W.R.; Craig, A.G.; Groebe, D.R.; Abramson, S.N.; McIntosh, J.M. alpha-Conotoxin EI, a new nicotinic acetylcholine receptor antagonist with novel selectivity. Biochemistry 1995, 34, 14519–14526. [Google Scholar]
  35. Hogg, R.C.; Miranda, L.P.; Craik, D.J.; Lewis, R.J.; Alewood, P.F.; Adams, D.J. Single amino acid substitutions in alpha-conotoxin PnIA shift selectivity for subtypes of the mammalian neuronal nicotinic acetylcholine receptor. J. Biol. Chem. 1999, 274, 36559–36564. [Google Scholar]
  36. Luo, S.; Nguyen, T.A.; Cartier, G.E.; Olivera, B.M.; Yoshikami, D.; McIntosh, J.M. Single-residue alteration in alpha-conotoxin PnIA switches its nAChR subtype selectivity. Biochemistry 1999, 38, 14542–14548. [Google Scholar]
  37. McIntosh, J.M.; Dowell, C.; Watkins, M.; Garrett, J.E.; Yoshikami, D.; Olivera, B.M. Alpha-conotoxin GIC from Conus geographus, a novel peptide antagonist of nicotinic acetylcholine receptors. J. Biol. Chem. 2002, 277, 33610–33615. [Google Scholar]
  38. Cartier, G.E.; Yoshikami, D.; Gray, W.R.; Luo, S.; Olivera, B.M.; McIntosh, J.M. A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J. Biol. Chem. 1996, 271, 7522–7528. [Google Scholar]
  39. McIntosh, J.M.; Azam, L.; Staheli, S.; Dowell, C.; Lindstrom, J.M.; Kuryatov, A.; Garrett, J.E.; Marks, M.J.; Whiteaker, P. Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol. Pharmacol. 2004, 65, 944–952. [Google Scholar]
  40. Dowell, C.; Olivera, B.M.; Garrett, J.E.; Staheli, S.T.; Watkins, M.; Kuryatov, A.; Yoshikami, D.; Lindstrom, J.M.; McIntosh, J.M. Alpha-conotoxin PIA is selective for alpha6 subunit-containing nicotinic acetylcholine receptors. J. Neurosci. 2003, 23, 8445–8452. [Google Scholar]
  41. Lopez-Vera, E.; Jacobsen, R.B.; Ellison, M.; Olivera, B.M.; Teichert, R.W. A novel alpha conotoxin (alpha-PIB) isolated from C. purpurascens is selective for skeletal muscle nicotinic acetylcholine receptors. Toxicon 2007, 49, 1193–1199. [Google Scholar] [CrossRef] [PubMed]
  42. Dutertre, S.; Nicke, A.; Lewis, R.J. Beta2 subunit contribution to. 4/7 alpha-conotoxin binding to the nicotinic acetylcholine receptor. J. Biol. Chem. 2005, 280, 30460–30468. [Google Scholar] [CrossRef] [PubMed]
  43. Nicke, A.; Loughnan, M.L.; Millard, E.L.; Alewood, P.F.; Adams, D.J.; Daly, N.L.; Craik, D.J.; Lewis, R.J. Isolation, structure, and activity of GID, a novel alpha. 4/7-conotoxin with an extended N-terminal sequence. J. Biol. Chem. 2003, 278, 3137–3144. [Google Scholar] [PubMed]
  44. Nicke, A.; Wonnacott, S.; Lewis, R.J. Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes. Eur. J. Biochem. 2004, 271, 2305–2319. [Google Scholar]
  45. Loughnan, M.; Bond, T.; Atkins, A.; Cuevas, J.; Adams, D.J.; Broxton, N.M.; Livett, B.G.; Down, J.G.; Jones, A.; Alewood, P.F.; Lewis, R.J. alpha-conotoxin EpI, a novel sulfated peptide from Conus episcopatus that selectively targets neuronal nicotinic acetylcholine receptors. J. Biol. Chem. 1998, 273, 15667–15674. [Google Scholar]
  46. Nicke, A.; Samochocki, M.; Loughnan, M.L.; Bansal, P.S.; Maelicke, A.; Lewis, R.J. Alpha-conotoxins EpI and AuIB switch subtype selectivity and activity in native versus recombinant nicotinic acetylcholine receptors. FEBS Lett. 2003, 554, 219–223. [Google Scholar]
  47. Loughnan, M.L.; Nicke, A.; Jones, A.; Adams, D.J.; Alewood, P.F.; Lewis, R.J. Chemical and functional identification and characterization of novel sulfated alpha-conotoxins from the cone snail Conus anemone. J. Med. Chem. 2004, 47, 1234–1241. [Google Scholar]
  48. Vincler, M.; Wittenauer, S.; Parker, R.; Ellison, M.; Olivera, B.M.; McIntosh, J.M. Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc. Natl. Acad. Sci. USA 2006, 103, 17880–17884. [Google Scholar]
  49. Clark, R.J.; Fischer, H.; Nevin, S.T.; Adams, D.J.; Craik, D.J. The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1. J. Biol. Chem. 2006, 281, 23254–23263. [Google Scholar] [PubMed]
  50. Whiteaker, P.; Christensen, S.; Yoshikami, D.; Dowell, C.; Watkins, M.; Gulyas, J.; Rivier, J.; Olivera, B.M.; McIntosh, J.M. Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist. Biochemistry 2007, 46, 6628–6638. [Google Scholar] [PubMed]
  51. McIntosh, J.M.; Plazas, P.V.; Watkins, M.; Gomez-Casati, M.E.; Olivera, B.M.; Elgoyhen, A.B. A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9 alpha10 and alpha7 nicotinic cholinergic receptors. J. Biol. Chem. 2005, 280, 30107–30112. [Google Scholar] [PubMed]
  52. Talley, T.T.; Olivera, B.M.; Han, K.H.; Christensen, S.B.; Dowell, C.; Tsigelny, I.; Ho, K.Y.; Taylor, P.; McIntosh, J.M. Alpha-conotoxin OmIA is a potent ligand for the acetylcholine-binding protein as well as alpha3beta2 and alpha7 nicotinic acetylcholine receptors. J. Biol. Chem. 2006, 281, 24678–24686. [Google Scholar]
  53. Dutertre, S.; Ulens, C.; Buttner, R.; Fish, A.; van Elk, R.; Kendel, Y.; Hopping, G.; Alewood, P.F.; Schroeder, C.; Nicke, A.; Smit, A.B.; Sixma, T.K.; Lewis, R.J. AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity. EMBO J. 2007, 26, 3858–3867. [Google Scholar]
  54. Peng, C.; Han, Y.; Sanders, T.; Chew, G.; Liu, J.; Hawrot, E.; Chi, C.; Wang, C. alpha4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors. Peptides 2008, 29, 1700–1707. [Google Scholar] [CrossRef] [PubMed]
  55. Lopez-Vera, E.; Aguilar, M.B.; Schiavon, E.; Marinzi, C.; Ortiz, E.; Restano Cassulini, R.; Batista, C.V.; Possani, L.D.; Heimer de la Cotera, E.P.; Peri, F.; Becerril, B.; Wanke, E. Novel alpha-conotoxins from Conus spurius and the alpha-conotoxin EI share high-affinity potentiation and low-affinity inhibition of nicotinic acetylcholine receptors. FEBS J. 2007, 274, 3972–3985. [Google Scholar]
  56. Dwoskin, L.P.; Crooks, P.A. Competitive neuronal nicotinic receptor antagonists: A new direction for drug discovery. J. Pharmacol. Exp. Ther. 2001, 298, 395–402. [Google Scholar]
  57. Lukas, R.J. Pharmacological distinctions between functional nicotinic acetylcholine receptors on the PC12 rat pheochromocytoma and the TE671 human medulloblastoma. J. Pharmacol. Exp. Ther. 1989, 251, 175–182. [Google Scholar]
  58. Decker, M.W.; Anderson, D.J.; Brioni, J.D.; Donnelly-Roberts, D.L.; Kang, C.H.; O'Neill, A.B.; Piattoni-Kaplan, M.; Swanson, S.; Sullivan, J.P. Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors. Eur. J. Pharmacol. 1995, 280, 79–89. [Google Scholar]
  59. Fitch, R.W.; Xiao, Y.; Kellar, K.J.; Daly, J.W. Membrane potential fluorescence: A rapid and highly sensitive assay for nicotinic receptor channel function. Proc. Natl. Acad. Sci. USA 2003, 100, 4909–4914. [Google Scholar]
  60. Aiyar, V.N.; Benn, M.H.; Hanna, T.; Jacyno, J.; Roth, S.H.; Wilkens, J.L. The principal toxin of Delphinium brownii Rydb., and its mode of action. Experientia 1979, 35, 1367–1368. [Google Scholar] [CrossRef] [PubMed]
  61. Macallan, D.R.; Lunt, G.G.; Wonnacott, S.; Swanson, K.L.; Rapoport, H.; Albuquerque, E.X. Methyllycaconitine and (+)-anatoxin-a differentiate between nicotinic receptors in vertebrate and invertebrate nervous systems. FEBS Lett. 1988, 226, 357–363. [Google Scholar]
  62. Ward, J.M.; Cockcroft, V.B.; Lunt, G.G.; Smillie, F.S.; Wonnacott, S. Methyllycaconitine: A selective probe for neuronal alpha-bungarotoxin binding sites. FEBS Lett. 1990, 270, 45–48. [Google Scholar]
  63. Kukel, C.F.; Jennings, K.R. Delphinium alkaloids as inhibitors of alpha-bungarotoxin binding to rat and insect neural membranes. Can. J. Physiol. Pharmacol. 1994, 72, 104–107. [Google Scholar]
  64. Dobelis, P.; Madl, J.E.; Pfister, J.A.; Manners, G.D.; Walrond, J.P. Effects of Delphinium alkaloids on neuromuscular transmission. J. Pharmacol. Exp. Ther. 1999, 291, 538–546. [Google Scholar]
  65. Pfister, J.A.; Gardner, D.R.; Panter, K.E.; Manners, G.D.; Ralphs, M.H.; Stegelmeier, B.L.; Schoch, T.K. Larkspur (Delphinium spp.) poisoning in livestock. J. Nat. Toxins 1999, 8, 81–94. [Google Scholar] [PubMed]
  66. Stromgaard, K. Natural products as tools for studies of ligand-gated ion channels. Chem. Rec. 2005, 5, 229–239. [Google Scholar]
  67. Hold, K.M.; Sirisoma, N.S.; Ikeda, T.; Narahashi, T.; Casida, J.E. Alpha-thujone (the active component of absinthe): Gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. Proc. Natl. Acad. Sci. USA 2000, 97, 3826–3831. [Google Scholar]
  68. Deiml, T.; Haseneder, R.; Zieglgansberger, W.; Rammes, G.; Eisensamer, B.; Rupprecht, R.; Hapfelmeier, G. Alpha-thujone reduces. 5-HT3 receptor activity by an effect on the agonist-reduced desensitization. Neuropharmacology 2004, 46, 192–201. [Google Scholar] [CrossRef] [PubMed]
  69. Chen, H.K.; Su, C.K. Endogenous activation of nicotinic receptors underlies sympathetic tone generation in neonatal rat spinal cord in vitro. Neuropharmacology 2006, 51, 1120–1128. [Google Scholar] [CrossRef] [PubMed]
  70. Erkkila, B.E.; Sedelnikova, A.V.; Weiss, D.S. Stoichiometric pore mutations of the GABAAR reveal a pattern of hydrogen bonding with picrotoxin. Biophys. J. 2008, 94, 4299–4306. [Google Scholar]
  71. Charon, S.; Taly, A.; Rodrigo, J.; Perret, P.; Goeldner, M. Binding Modes of Noncompetitive GABA-Channel Blockers Revisited Using Engineered Affinity-Labeling Reactions Combined with New Docking Studies (dagger). J. Agric. Food Chem. 2010. [Google Scholar]
  72. Johnson, J.W.; Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 1987, 325, 529–531. [Google Scholar]
  73. England, L.J.; Imperial, J.; Jacobsen, R.; Craig, A.G.; Gulyas, J.; Akhtar, M.; Rivier, J.; Julius, D.; Olivera, B.M. Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails. Science. 1998, 281, 575–578. [Google Scholar]
  74. Yan, D.; White, M.M. Interaction of d-tubocurarine analogs with mutant 5-HT(3) receptors. Neuropharmacology 2002, 43, 367–373. [Google Scholar] [CrossRef] [PubMed]
  75. Griffith, H.R.; Johnson, G. The use of curare in general anasthesia. Anesthesiology 1942, 3, 418–420. [Google Scholar]
  76. Parks, T.N.; Mueller, A.L.; Artman, L.D.; Albensi, B.C.; Nemeth, E.F.; Jackson, H.; Jasys, V.J.; Saccomano, N.A.; Volkmann, R.A. Arylamine toxins from funnel-web spider (Agelenopsis aperta) venom antagonize N-methyl-D-aspartate receptor function in mammalian brain. J. Biol. Chem. 1991, 266, 21523–21529. [Google Scholar] [PubMed]
  77. Kiskin, N.I.; Chizhmakov, I.V.; Tsyndrenko, A.; Mueller, A.L.; Jackson, H.; Krishtal, O.A. A highly potent and selective N-methyl-D-aspartate receptor antagonist from the venom of the Agelenopsis aperta spider. Neuroscience 1992, 51, 11–18. [Google Scholar] [CrossRef] [PubMed]
  78. Frydenvang, K.; Lash, L.L.; Naur, P.; Postila, P.A.; Pickering, D.S.; Smith, C.M.; Gajhede, M.; Sasaki, M.; Sakai, R.; Pentikainen, O.T.; Swanson, G.T.; Kastrup, J.S. Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist. 8,9-dideoxyneodysiherbaine. J. Biol. Chem. 2009, 284, 14219–14229. [Google Scholar] [PubMed]
  79. Rajendra, W.; Armugam, A.; Jeyaseelan, K. Toxins in anti-nociception and anti-inflammation. Toxicon 2004, 44, 1–17. [Google Scholar]
  80. Sheng, Z.; Prorok, M.; Castellino, F.J. Specific determinants of conantokins that dictate their selectivity for the NR2B subunit of N-methyl-D-aspartate receptors. Neuroscience 2010, 170, 703–710. [Google Scholar]
  81. Skjaerbaek, N.; Nielsen, K.J.; Lewis, R.J.; Alewood, P.; Craik, D.J. Determination of the solution structures of conantokin-G and conantokin-T by CD and NMR spectroscopy. J. Biol. Chem. 1997, 272, 2291–2299. [Google Scholar]
  82. Dai, Q.; Xiao, C.; Dong, M.; Liu, Z.; Sheng, Z.; Castellino, F.J.; Prorok, M. Non-strict strand orientation of the Ca2+-induced dimerization of a conantokin peptide variant with sequence-shifted gamma-carboxyglutamate residues. Peptides 2009, 30, 866–872. [Google Scholar]
  83. Lodge, D. The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology 2009, 56, 6–21. [Google Scholar]
  84. Sakai, R.; Minato, S.; Koike, K.; Jimbo, M.; Kamiya, H. Cellular and subcellular localization of kainic acid in the marine red alga Digenea simplex. Cell Tissue Res. 2005, 322, 491–502. [Google Scholar]
  85. Swanson, G.T.; Green, T.; Sakai, R.; Contractor, A.; Che, W.; Kamiya, H.; Heinemann, S.F. Differential activation of individual subunits in heteromeric kainate receptors. Neuron 2002, 34, 589–598. [Google Scholar]
  86. Savchenko, H.A.; Vasylevs'kyi, A.A.; Pluzhnykov, K.A.; Korol'kova Iu, V.; Mamenko, M.V.; Volkova, T.M.; Maksymiuk, O.P.; Boichuk Ia, A.; Hrishyn Ie, V.; Kryshtal, O.O. Peptide components of Geolycosa spider venom modulate P2X receptor activity of rat sensory neurons. Fiziol. Zh. 2009, 55, 11–16. [Google Scholar]
  87. Grishin, E.V.; Savchenko, G.A.; Vassilevski, A.A.; Korolkova, Y.V.; Boychuk, Y.A.; Viatchenko-Karpinski, V.Y.; Nadezhdin, K.D.; Arseniev, A.S.; Pluzhnikov, K.A.; Kulyk, V.B.; Voitenko, N.V.; Krishtal, O.O. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann. Neurol. 2010, 67, 680–683. [Google Scholar]
  88. Patyar, S.; Joshi, R.; Byrav, D.S.; Prakash, A.; Medhi, B.; Das, B.K. Bacteria in cancer therapy: A novel experimental strategy. J. Biomed. Sci. 2010, 17, 21. [Google Scholar]
  89. Shapira, A.; Benhar, I. Toxin-Based Therapeutic Approaches. Toxins 2010, 2, 2519–2583. [Google Scholar]
  90. Tutka, P.; Zatonski, W. Cytisine for the treatment of nicotine addiction: From a molecule to therapeutic efficacy. Pharmacol. Rep. 2006, 58, 777–798. [Google Scholar]
  91. Cohen, C.; Bergis, O.E.; Galli, F.; Lochead, A.W.; Jegham, S.; Biton, B.; Leonardon, J.; Avenet, P.; Sgard, F.; Besnard, F.; Graham, D.; Coste, A.; Oblin, A.; Curet, O.; Voltz, C.; Gardes, A.; Caille, D.; Perrault, G.; George, P.; Soubrie, P.; Scatton, B. SSR591813, a novel selective and partial alpha4beta2 nicotinic receptor agonist with potential as an aid to smoking cessation. J. Pharmacol. Exp. Ther. 2003, 306, 407–420. [Google Scholar]
  92. Martin, L.F.; Kem, W.R.; Freedman, R. Alpha-7 nicotinic receptor agonists: Potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl) 2004, 174, 54–64. [Google Scholar] [PubMed]
  93. Wei, S.; Qiu, L.; Chen, Z.H.; Xu, M.C. Effect observation of Snake venom point injection in the treatment of scapulohumeral periarthritis. Chin. J. Infor. Traditional Chin. Med. 2007, 14, 68–96. [Google Scholar]
  94. Grozio, A.; Paleari, L.; Catassi, A.; Servent, D.; Cilli, M.; Piccardi, F.; Paganuzzi, M.; Cesario, A.; Granone, P.; Mourier, G.; Russo, P. Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: A promising prospective in anti-cancer drug development. Int. J. Cancer. 2008, 122, 1911–1915. [Google Scholar]
  95. Spindel, E.R. Is nicotine the estrogen of lung cancer? Am. J. Respir. Crit. Care. Med. 2009, 179, 1081–1082. [Google Scholar] [CrossRef] [PubMed]
  96. Paleari, L.; Negri, E.; Catassi, A.; Cilli, M.; Servent, D.; D'Angelillo, R.; Cesario, A.; Russo, P.; Fini, M. Inhibition of nonneuronal alpha7-nicotinic receptor for lung cancer treatment. Am. J. Respir. Crit. Care. Med. 2009, 179, 1141–1150. [Google Scholar]
  97. Catassi, A.; Paleari, L.; Servent, D.; Sessa, F.; Dominioni, L.; Ognio, E.; Cilli, M.; Vacca, P.; Mingari, M.; Gaudino, G.; Bertino, P.; Paolucci, M.; Calcaterra, A.; Cesario, A.; Granone, P.; Costa, R.; Ciarlo, M.; Alama, A.; Russo, P. Targeting alpha7-nicotinic receptor for the treatment of pleural mesothelioma. Eur. J. Cancer. 2008, 44, 2296–2311. [Google Scholar]
  98. Russo, P.; Catassi, A.; Cesario, A.; Servent, D. Development of novel therapeutic strategies for lung cancer: Targeting the cholinergic system. Curr. Med. Chem. 2006, 13, 3493–3512. [Google Scholar]
  99. Chen, Z.X.; Zhang, H.L.; Gu, Z.L.; Chen, B.W.; Han, R.; Reid, P.F.; Raymond, L.N.; Qin, Z.H. A long-form alpha-neurotoxin from cobra venom produces potent opioid-independent analgesia. Acta Pharmacol. Sin. 2006, 27, 402–408. [Google Scholar]
  100. Reid, P.F. Alpha-cobratoxin as a possible therapy for multiple sclerosis: A review of the literature leading to its development for this application. Crit. Rev. Immunol. 2007, 27, 291–302. [Google Scholar]
  101. Zhang, H.L.; Han, R.; Chen, Z.X.; Gu, Z.L.; Reid, P.F.; Raymond, L.N.; Qin, Z.H. Analgesic effects of receptin, a chemically modified cobratoxin from Thailand cobra venom. Neurosci. Bull. 2006, 22, 267–273. [Google Scholar]
  102. Nevin, S.T.; Clark, R.J.; Klimis, H.; Christie, M.J.; Craik, D.J.; Adams, D.J. Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins? Mol. Pharmacol. 2007, 72, 1406–1410. [Google Scholar] [CrossRef] [PubMed]
  103. Callaghan, B.; Haythornthwaite, A.; Berecki, G.; Clark, R.J.; Craik, D.J.; Adams, D.J. Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J. Neurosci. 2008, 28, 10943–10951. [Google Scholar] [PubMed]
  104. Azam, L.; McIntosh, J.M. Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors. Acta. Pharmacol. Sin. 2009, 30, 771–783. [Google Scholar]
  105. Tuba, Z.; Maho, S.; Vizi, E.S. Synthesis and structure-activity relationships of neuromuscular blocking agents. Curr. Med. Chem. 2002, 9, 1507–1536. [Google Scholar]
  106. Hughes, T. The early history of myasthenia gravis. Neuromuscul. Disord. 2005, 15, 878–886. [Google Scholar]
  107. Vincent, A. Unravelling the pathogenesis of myasthenia gravis. Nat. Rev. Immunol. 2002, 2, 797–804. [Google Scholar]
  108. Engel, A.G.; Sine, S.M. Current understanding of congenital myasthenic syndromes. Curr. Opin. Pharmacol. 2005, 5, 308–321. [Google Scholar]
  109. Garcia-Colunga, J.; Miledi, R. Modulation of nicotinic acetylcholine receptors by strychnine. Proc. Natl. Acad. Sci. USA 1999, 96, 4113–4118. [Google Scholar]
  110. Verkman, A.S.; Galietta, L.J. Chloride channels as drug targets. Nat. Rev. Drug. Discov. 2009, 8, 153–171. [Google Scholar]
  111. Laube, B.; Maksay, G.; Schemm, R.; Betz, H. Modulation of glycine receptor function: A novel approach for therapeutic intervention at inhibitory synapses? Trends Pharmacol. Sci. 2002, 23, 519–527. [Google Scholar] [CrossRef] [PubMed]
  112. Walstab, J.; Rappold, G.; Niesler, B. 5-HT(3) receptors: Role in disease and target of drugs. Pharmacol. Ther. 2010, 128, 146–169. [Google Scholar]
  113. Koller, M.; Urwyler, S. Novel N-methyl-D-aspartate receptor antagonists: A review of compounds patented since. 2006. Expert. Opin. Ther. Pat. 2010, 20, 1683–1702. [Google Scholar] [CrossRef] [PubMed]
  114. Malmberg, A.B.; Gilbert, H.; McCabe, R.T.; Basbaum, A.I. Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T. Pain 2003, 101, 109–116. [Google Scholar]
  115. Hama, A.; Sagen, J. Antinociceptive effects of the marine snail peptides conantokin-G and conotoxin MVIIA alone and in combination in rat models of pain. Neuropharmacology 2009, 56, 556–563. [Google Scholar]
  116. Jimenez, E.C.; Donevan, S.; Walker, C.; Zhou, L.M.; Nielsen, J.; Cruz, L.J.; Armstrong, H.; White, H.S.; Olivera, B.M. Conantokin-L, a new NMDA receptor antagonist: Determinants for anticonvulsant potency. Epilepsy Res. 2002, 51, 73–80. [Google Scholar]
  117. Prorok, M.; Castellino, F.J. The molecular basis of conantokin antagonism of NMDA receptor function. Curr. Drug. Targets. 2007, 8, 633–642. [Google Scholar]
  118. Swanson, G.T.; Sakai, R. Ligands for ionotropic glutamate receptors. Prog. Mol. SubCell Biol. 2009, 46, 123–157. [Google Scholar]
  119. Li, Z.; Liang, D.; Chen, L. Potential therapeutic targets for ATP-gated P2X receptor ion channels. Assay Drug. Dev. Technol. 2008, 6, 277–284. [Google Scholar]
  120. Gunosewoyo, H.; Kassiou, M. P2X purinergic receptor ligands: Recently patented compounds. Expert Opin. Ther. Pat. 2010, 20, 625–646. [Google Scholar]
  121. Ryan, T.J.; Grant, S.G. The origin and evolution of synapses. Nat. Rev. Neurosci. 2009, 10, 701–712. [Google Scholar]
  122. Tasneem, A.; Iyer, L.M.; Jakobsson, E.; Aravind, L. Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels. Genome. Biol. 2005, 6, R4. [Google Scholar]
  123. Bocquet, N.; Prado de Carvalho, L.; Cartaud, J.; Neyton, J.; Le Poupon, C.; Taly, A.; Grutter, T.; Changeux, J.P.; Corringer, P.J. A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature 2007, 445, 116–119. [Google Scholar]
  124. Chen, G.Q.; Cui, C.; Mayer, M.L.; Gouaux, E. Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature 1999, 402, 817–821. [Google Scholar]
  125. Osborne, R.H. Insect neurotransmission: Neurotransmitters and their receptors. Pharmacol. Ther. 1996, 69, 117–142. [Google Scholar]
  126. Ryten, M.; Koshi, R.; Knight, G.E.; Turmaine, M.; Dunn, P.; Cockayne, D.A.; Ford, A.P.; Burnstock, G. Abnormalities in neuromuscular junction structure and skeletal muscle function in mice lacking the P2X2 nucleotide receptor. Neuroscience 2007, 148, 700–711. [Google Scholar]
  127. Adams, D.J.; Alewoodb, P.F.; Craikb, D.J.; Drinkwaterc, R.D.; Lewis, R.J. Conotoxins and Their Potential Pharmaceutical Applications. Drug Dev. Res. 1999, 46, 219–234. [Google Scholar] [CrossRef]
  128. Moise, L.; Piserchio, A.; Basus, V.J.; Hawrot, E. NMR structural analysis of alpha-bungarotoxin and its complex with the principal alpha-neurotoxin-binding sequence on the alpha.7 subunit of a neuronal nicotinic acetylcholine receptor. J. Biol. Chem. 2002, 277, 12406–12417. [Google Scholar] [PubMed]
  129. Samson, A.; Scherf, T.; Eisenstein, M.; Chill, J.; Anglister, J. The mechanism for acetylcholine receptor inhibition by alpha-neurotoxins and species-specific resistance to alpha-bungarotoxin revealed by NMR. Neuron 2002, 35, 319–332. [Google Scholar]
  130. Osaka, H.; Malany, S.; Molles, B.E.; Sine, S.M.; Taylor, P. Pairwise electrostatic interactions between alpha-neurotoxins and gamma, delta, and epsilon subunits of the nicotinic acetylcholine receptor. J. Biol. Chem. 2000, 275, 5478–5484. [Google Scholar] [PubMed]
  131. Servent, D.; Menez, A. Snake neurotoxins that interact with nicotinic acetylcholine receptors. In Handbook of Neurotoxicology; Humana Press Inc.: Totowa, NJ, USA, 2001; pp. 385–425. [Google Scholar]
  132. Zeng, H.; Hawrot, E. NMR-based binding screen and structural analysis of the complex formed between alpha-cobratoxin and an 18-mer cognate peptide derived from the alpha 1 subunit of the nicotinic acetylcholine receptor from Torpedo californica. J. Biol. Chem. 2002, 277, 37439–37445. [Google Scholar] [CrossRef] [PubMed]
  133. Low, B.W.; Preston, H.S.; Sato, A.; Rosen, L.S.; Searl, J.E.; Rudko, A.D.; Richardson, J.S. Three dimensional structure of erabutoxin b neurotoxic protein: Inhibitor of acetylcholine receptor. Proc. Natl. Acad. Sci. USA 1976, 73, 2991–2994. [Google Scholar]
  134. Miwa, J.M.; Ibanez-Tallon, I.; Crabtree, G.W.; Sanchez, R.; Sali, A.; Role, L.W.; Heintz, N. lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron 1999, 23, 105–114. [Google Scholar]
  135. Lyukmanova, E.N.; Shenkarev, Z.O.; Shulepko, M.A.; Mineev, K.S.; D'Hoedt, D.; Kasheverov, I.E.; Filkin, S.Y.; Krivolapova, A.P.; Janickova, H.; Dolezal, V.; Dolgikh, D.A.; Arseniev, A.S.; Bertrand, D.; Tsetlin, V.I.; Kirpichnikov, M.P. Nmr Structure and Action on Nicotinic Acetylcholine Receptors of Water-Soluble Domain of Human Lynx1. J. Biol. Chem. 2011. [Google Scholar]
  136. Pawlak, J.; Mackessy, S.P.; Fry, B.G.; Bhatia, M.; Mourier, G.; Fruchart-Gaillard, C.; Servent, D.; Menez, R.; Stura, E.; Menez, A.; Kini, R.M. Denmotoxin, a three-finger toxin from the colubrid snake Boiga dendrophila (Mangrove Catsnake) with bird-specific activity. J. Biol. Chem. 2006, 281, 29030–29041. [Google Scholar]
  137. Tsai, M.C.; Hsieh, W.H.; Smith, L.A.; Lee, C.Y. Effects of waglerin-I on neuromuscular transmission of mouse nerve-muscle preparations. Toxicon 1995, 33, 363–371. [Google Scholar]
  138. Utkin, Y.N.; Kukhtina, V.V.; Kryukova, E.V.; Chiodini, F.; Bertrand, D.; Methfessel, C.; Tsetlin, V.I. "Weak toxin" from Naja kaouthia is a nontoxic antagonist of alpha. 7 and muscle-type nicotinic acetylcholine receptors. J. Biol. Chem. 2001, 276, 15810–15815. [Google Scholar] [PubMed]
  139. Nirthanan, S.; Charpantier, E.; Gopalakrishnakone, P.; Gwee, M.C.; Khoo, H.E.; Cheah, L.S.; Bertrand, D.; Kini, R.M. Candoxin, a novel toxin from Bungarus candidus, is a reversible antagonist of muscle (alphabetagammadelta ) but a poorly reversible antagonist of neuronal alpha. 7 nicotinic acetylcholine receptors. J. Biol. Chem. 2002, 277, 17811–17820. [Google Scholar] [PubMed]
  140. Joubert, F.J.; Taljaard, N. Naja haje haje (Egyptian cobra) venom. Some properties and the complete primary structure of three toxins (CM-2, CM-11 and CM-12). Eur. J. Biochem. 1978, 90, 359–367. [Google Scholar] [CrossRef] [PubMed]
  141. Harvey, A.L.; Hider, R.C.; Hodges, S.J.; Joubert, F.J. Structure-activity studies of homologues of short chain neurotoxins from Elapid snake venoms. Br. J. Pharmacol. 1984, 82, 709–716. [Google Scholar]
  142. Carlsson, F.H. Snake venom toxins. The primary structure of protein S4C11. A neurotoxin homologue from the venom of forest cobra (Naja melanoleuca). Biochim. Biophys. Acta. 1975, 400, 310–321. [Google Scholar] [PubMed]
  143. Joubert, F.J.; Taljaard, N. Some properties and the complete primary structures of two reduced and S-carboxymethylated polypeptides (S5C1 and S5C10) from Dendroaspis jamesoni kaimosae (Jameson's mamba) venom. Biochim. Biophys. Acta 1979, 579, 228–233. [Google Scholar]
  144. Aird, S.D.; Womble, G.C.; Yates, J.R., 3rd.; Griffin, P.R. Primary structure of gamma-bungarotoxin, a new postsynaptic neurotoxin from venom of Bungarus multicinctus. Toxicon 1999, 37, 609–625. [Google Scholar] [CrossRef] [PubMed]
  145. Poh, S.L.; Mourier, G.; Thai, R.; Armugam, A.; Molgo, J.; Servent, D.; Jeyaseelan, K.; Menez, A. A synthetic weak neurotoxin binds with low affinity to Torpedo and chicken alpha7 nicotinic acetylcholine receptors. Eur. J. Biochem. 2002, 269, 4247–4256. [Google Scholar]
  146. Chang, L.; Lin, S.; Wang, J.; Hu, W.P.; Wu, B.; Huang, H. Structure-function studies on Taiwan cobra long neurotoxin homolog. Biochim. Biophys. Acta. 2000, 1480, 293–301. [Google Scholar]
  147. Harvey, A.L.; Rodger, I.W. Reversibility of neuromuscular blockade produced by toxins isolated from the venom of the seasnake Laticauda semifasciata. Toxicon 1978, 16, 219–225. [Google Scholar]
  148. Brier, T.J.; Mellor, I.R.; Tikhonov, D.B.; Neagoe, I.; Shao, Z.; Brierley, M.J.; Stromgaard, K.; Jaroszewski, J.W.; Krogsgaard-Larsen, P.; Usherwood, P.N. Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors. Mol. Pharmacol. 2003, 64, 954–964. [Google Scholar]
  149. Shu, Q.; Liang, S.P. Purification and characterization of huwentoxin-II, a neurotoxic peptide from the venom of the Chinese bird spider Selenocosmia huwena. J. Pept. Res. 1999, 53, 486–491. [Google Scholar]
  150. Liang, S.P.; Zhang, D.Y.; Pan, X.; Chen, Q.; Zhou, P.A. Properties and amino acid sequence of huwentoxin-I, a neurotoxin purified from the venom of the Chinese bird spider Selenocosmia huwena. Toxicon 1993, 31, 969–978. [Google Scholar]
  151. Daly, J.W. Nicotinic agonists, antagonists, and modulators from natural sources. Cell Mol. Neurobiol. 2005, 25, 513–552. [Google Scholar] [CrossRef] [PubMed]
  152. Barlow, R.B.; McLeod, L.J. Some studies on cytisine and its methylated derivatives. Br. J. Pharmacol. 1969, 35, 161–174. [Google Scholar]
  153. Osswald, J.; Rellan, S.; Gago, A.; Vasconcelos, V. Toxicology and detection methods of the alkaloid neurotoxin produced by cyanobacteria, anatoxin-a. Environ. Int. 2007, 33, 1070–1089. [Google Scholar]
  154. Merel, S.; Clement, M.; Thomas, O. State of the art on cyanotoxins in water and their behaviour towards chlorine. Toxicon 2010, 55, 677–691. [Google Scholar]
  155. Araoz, R.; Vilarino, N.; Botana, L.M.; Molgo, J. Ligand-binding assays for cyanobacterial neurotoxins targeting cholinergic receptors. Anal. Bioanal. Chem. 2010, 397, 1695–1704. [Google Scholar]
  156. Badio, B.; Daly, J.W. Epibatidine, a potent analgetic and nicotinic agonist. Mol. Pharmacol. 1994, 45, 563–569. [Google Scholar]
  157. Kem, W.R.; Mahnir, V.M.; Papke, R.L.; Lingle, C.J. Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors. J. Pharmacol. Exp. Ther. 1997, 283, 979–992. [Google Scholar]
  158. Spivak, C.E.; Maleque, M.A.; Oliveira, A.C.; Masukawa, L.M.; Tokuyama, T.; Daly, J.W.; Albuquerque, E.X. Actions of the histrionicotoxins at the ion channel of the nicotinic acetylcholine receptor and at the voltage-sensitive ion channels of muscle membranes. Mol. Pharmacol. 1982, 21, 351–361. [Google Scholar]
  159. Bick, R.C.; Gillard, J.W.; Leow, H.-M. Alkaloids of Darlingia ferruginea. Australian. J. Chem. 1979, 32, 2537–2543. [Google Scholar] [CrossRef]
  160. Van Maanen, E.F. The antagonism between acetylcholine and the curare alkaloids, d-tubocurarine, c-curarine-I, c-toxiferine-II and beta-erythroidine in the rectus abdominis of the frog. J. Pharmacol. Exp. Ther. 1950, 99, 255–264. [Google Scholar] [PubMed]
  161. Jensen, A.A.; Zlotos, D.P.; Liljefors, T. Pharmacological characteristics and binding modes of caracurine V analogues and related compounds at the neuronal alpha7 nicotinic acetylcholine receptor. J. Med. Chem. 2007, 50, 4616–4629. [Google Scholar]
  162. Tay, G. Diallyl nor-Toxiferine -a New Relaxant. Singapore Med. J. 1963, 141, 90–92. [Google Scholar]
  163. Kosuge, T.; Tsuji, K.; Hirai, K. Isolation of neosurugatoxin from the Japanese ivory shell, Babylonia japonica. Chem. Pharm. Bull (Tokyo) 1982, 30, 3255–3259. [Google Scholar] [PubMed]
  164. Hayashi, E.; Isogai, M.; Kagawa, Y.; Takayanagi, N.; Yamada, S. Neosurugatoxin, a specific antagonist of nicotinic acetylcholine receptors. J. Neurochem. 1984, 42, 1491–1494. [Google Scholar] [CrossRef] [PubMed]
  165. Hayashi, E.; Yamada, S. Pharmacological studies on surugatoxin, the toxic principle from Japanese ivory mollusc (Babylonia japonica). Br. J. Pharmacol. 1975, 53, 207–215. [Google Scholar]
  166. Tornoe, C.; Bai, D.; Holden-Dye, L.; Abramson, S.N.; Sattelle, D.B. Actions of neurotoxins (bungarotoxins, neosurugatoxin and lophotoxins) on insect and nematode nicotinic acetylcholine receptors. Toxicon 1995, 33, 411–424. [Google Scholar]
  167. Maciulaitis, R.; Kontrimaviciute, V.; Bressolle, F.M.; Briedis, V. Ibogaine, an anti-addictive drug: Pharmacology and time to go further in development. A narrative review. Hum. Exp. Toxicol. 2008, 27, 181–194. [Google Scholar] [CrossRef] [PubMed]
  168. Mash, D.C.; Kovera, C.A.; Buck, B.E.; Norenberg, M.D.; Shapshak, P.; Hearn, W.L.; Sanchez-Ramos, J. Medication development of ibogaine as a pharmacotherapy for drug dependence. Ann. N.Y. Acad. Sci. 1998, 844, 274–292. [Google Scholar]
  169. Matsubayashi, H.; Alkondon, M.; Pereira, E.F.; Swanson, K.L.; Albuquerque, E.X. Strychnine: A potent competitive antagonist of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal neurons. J. Pharmacol. Exp. Ther. 1998, 284, 904–913. [Google Scholar]
  170. Francis, M.M.; Cheng, E.Y.; Weiland, G.A.; Oswald, R.E. Specific activation of the alpha. 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine. Mol. Pharmacol. 2001, 60, 71–79. [Google Scholar] [PubMed]
  171. Haefely, W. The effects of various "nicotine-like" agents in the cat superior cervical ganglion in situ. Naunyn. Schmiedebergs. Arch. Pharmacol. 1974, 281, 93–117. [Google Scholar] [CrossRef] [PubMed]
  172. Sakurai, Y.; Takano, Y.; Kohjimoto, Y.; Honda, K.; Kamiya, H.O. Enhancement of [3H]dopamine release and its [3H]metabolites in rat striatum by nicotinic drugs. Brain. Res. 1982, 242, 99–106. [Google Scholar]
  173. Rozman, K.B.; Araoz, R.; Sepcic, K.; Molgo, J.; Suput, D. Parazoanthoxanthin A blocks Torpedo nicotinic acetylcholine receptors. Chem. Biol. Interact. 2010, 187, 384–387. [Google Scholar]
  174. Culver, P.; Burch, M.; Potenza, C.; Wasserman, L.; Fenical, W.; Taylor, P. Structure-activity relationships for the irreversible blockade of nicotinic receptor agonist sites by lophotoxin and congeneric diterpene lactones. Mol. Pharmacol. 1985, 28, 436–444. [Google Scholar]
  175. Culver, P.; Fenical, W.; Taylor, P. Lophotoxin irreversibly inactivates the nicotinic acetylcholine receptor by preferential association at one of the two primary agonist sites. J. Biol. Chem. 1984, 259, 3763–3770. [Google Scholar]
  176. Culver, P.; Jacobs, R.S. Lophotoxin: A neuromuscular acting toxin from the sea whip (Lophogorgia rigida). Toxicon 1981, 19, 825–830. [Google Scholar] [CrossRef] [PubMed]
  177. Fenical, W.; Okuda, R.K.; Bandurraga, M.M.; Culver, P.; Jacobs, R.S. Lophotoxin: A novel neuromuscular toxin from Pacific sea whips of the genus Lophogorgia. Science 1981, 212, 1512–1514. [Google Scholar] [PubMed]
  178. Luetje, C.W.; Wada, K.; Rogers, S.; Abramson, S.N.; Tsuji, K.; Heinemann, S.; Patrick, J. Neurotoxins distinguish between different neuronal nicotinic acetylcholine receptor subunit combinations. J. Neurochem. 1990, 55, 632–640. [Google Scholar]
  179. Abramson, S.N.; Li, Y.; Culver, P.; Taylor, P. An analog of lophotoxin reacts covalently with Tyr190 in the alpha-subunit of the nicotinic acetylcholine receptor. J. Biol. Chem. 1989, 264, 12666–12672. [Google Scholar]
  180. Holmskov, U.; Laursen, S.B.; Malhotra, R.; Wiedemann, H.; Timpl, R.; Stuart, G.R.; Tornoe, I.; Madsen, P.S.; Reid, K.B.; Jensenius, J.C. Comparative study of the structural and functional properties of a bovine plasma C-type lectin, collectin-43, with other collectins. Biochem. J. 1995, 305, 889–896. [Google Scholar] [PubMed]
  181. Johnston, G.A.; Hanrahan, J.R.; Chebib, M.; Duke, R.K.; Mewett, K.N. Modulation of ionotropic GABA receptors by natural products of plant origin. Adv. Pharmacol. 2006, 54, 285–316. [Google Scholar]
  182. Takemoto, T.; Nakajima, T.; Sakuma, R. Isolation of a Flycidal Constituent "Ibotenic Acid" from Amanita Muscaria and A. Pantherina. Yakugaku. Zasshi. 1964, 84, 1233–1234. [Google Scholar] [PubMed]
  183. Takemoto, T.; Nakajima, T.; Yokobe, T. Structure of Ibotenic Acid. Yakugaku. Zasshi. 1964, 84, 1232–1233. [Google Scholar]
  184. Casarett, L.J.; Doull, J.; Klaassen, C.D. Casarett and. Doull's Toxicology: The Basic Science of Poisons, 7th ed; McGraw-Hill Medical: London, UK, 2008; p. 1236. [Google Scholar]
  185. Shin-ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.; Seto, H. Structure of kaitocephalin, a novel glutamate receptor antagonist produced by Eupenicillium shearii. Tetrahedron. Lett. 1997, 36, 7079–7082. [Google Scholar]
  186. Limon, A.; Reyes-Ruiz, J.M.; Vaswani, R.G.; Chamberlin, A.R.; Miledi, R. Kaitocephalin antagonism of glutamate receptors expressed in Xenopus oocytes. ACS. Chem. Neurosci. 2010, 1, 175–181. [Google Scholar] [CrossRef] [PubMed]
  187. Reis, H.J.; Prado, M.A.; Kalapothakis, E.; Cordeiro, M.N.; Diniz, C.R.; De Marco, L.A.; Gomez, M.V.; Romano-Silva, M.A. Inhibition of glutamate uptake by a polypeptide toxin (phoneutriatoxin. 3-4) from the spider Phoneutria nigriventer. Biochem. J. 1999, 343, 413–418. [Google Scholar] [CrossRef] [PubMed]
  188. Mafra, R.A.; Figueiredo, S.G.; Diniz, C.R.; Cordeiro, M.N.; Cruz, J.D.; De Lima, M.E. PhTx4, a new class of toxins from Phoneutria nigriventer spider venom, inhibits the glutamate uptake in rat brain synaptosomes. Brain. Res. 1999, 831, 297–300. [Google Scholar] [CrossRef] [PubMed]
  189. de Figueiredo, S.G.; de Lima, M.E.; Nascimento Cordeiro, M.; Diniz, C.R.; Patten, D.; Halliwell, R.F.; Gilroy, J.; Richardson, M. Purification and amino acid sequence of a highly insecticidal toxin from the venom of the brazilian spider Phoneutria nigriventer which inhibits NMDA-evoked currents in rat hippocampal neurones. Toxicon 2001, 39, 309–317. [Google Scholar]
  190. Piek, T. Neurotoxins from venoms of the Hymenoptera--twenty-five years of research in Amsterdam. Comp. Biochem. Physiol. C 1990, 96, 223–233. [Google Scholar]
  191. Clark, R.B.; Donaldson, P.L.; Gration, K.A.; Lambert, J.J.; Piek, T.; Ramsey, R.; Spanjer, W.; Usherwood, P.N. Block of locust muscle glutamate receptors by delta-philanthotoxin occurs after receptor activations. Brain. Res. 1982, 241, 105–114. [Google Scholar]
  192. Hagan, R.M.; Jones, B.J.; Jordan, C.C.; Tyers, M.B. Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat. Br. J. Pharmacol. 1990, 99, 227–232. [Google Scholar] [PubMed]
  193. Andersen, T.F.; Tikhonov, D.B.; Bolcho, U.; Bolshakov, K.; Nelson, J.K.; Pluteanu, F.; Mellor, I.R.; Egebjerg, J.; Stromgaard, K. Uncompetitive antagonism of AMPA receptors: Mechanistic insights from studies of polyamine toxin derivatives. J. Med. Chem. 2006, 49, 5414–5423. [Google Scholar]
  194. Rash, L.D.; Hodgson, W.C. Pharmacology and biochemistry of spider venoms. Toxicon 2002, 40, 225–254. [Google Scholar]
  195. Brackley, P.T.; Bell, D.R.; Choi, S.K.; Nakanishi, K.; Usherwood, P.N. Selective antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins. J. Pharmacol. Exp. Ther. 1993, 266, 1573–1580. [Google Scholar]
  196. Chiba, T.; Akizawa, T.; Matsukawa, M.; Pan-Hou, H.; Yoshioka, M. Finding of primitive polyamine toxins in the venom of a joro spider, Nephila clavata. Chem. Pharm. Bull (Tokyo) 1994, 42, 1864–1869. [Google Scholar] [PubMed]
  197. Sorkin, L.S.; Yaksh, T.L.; Doom, C.M. Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists. Anesthesiology. 2001, 95, 965–973. [Google Scholar]
  198. Gmelin, R. The free amino acids in the seeds of Acacia willardiana (Mimosaceae). Isolation of willardiin, a new plant amino acid which is probably L-beta-(3-uracil)-alpha-aminopropionic acid. Hoppe. Seylers. Z.Physiol. Chem. 1959, 316, 164–169. [Google Scholar] [CrossRef] [PubMed]
  199. Evans, R.H.; Jones, A.W.; Watkins, J.C. Willardiine: A potent quisqualate-like excitant. J. Physiol (Lond) 1980, 308, 71–72. [Google Scholar]
  200. Shinozaki, H.; Ishida, M. Excitatory amino acids: Physiological and pharmacological probes for neuroscience research. Acta. Neurobiol. Exp (Wars) 1993, 53, 43–51. [Google Scholar] [PubMed]
  201. Scallet, A.C.; Ye, X. Excitotoxic mechanisms of neurodegeneration in transmissible spongiform encephalopathies. Ann. N Y. Acad. Sci. 1997, 825, 194–205. [Google Scholar]
  202. Agrawal, B.B.; Goldstein, I.J. Protein-carbohydrate interaction. VI. Isolation of concanavalin A by specific adsorption on cross-linked dextran gels. Biochim. Biophys. Acta. 1967, 147, 262–271. [Google Scholar] [PubMed]
  203. Bowie, D.; Garcia, E.P.; Marshall, J.; Traynelis, S.F.; Lange, G.D. Allosteric regulation and spatial distribution of kainate receptors bound to ancillary proteins. J. Physiol. 2003, 547, 373–385. [Google Scholar]
  204. Boland, L.M.; Morrill, J.A.; Bean, B.P. omega-Conotoxin block of N-type calcium channels in frog and rat sympathetic neurons. J. Neurosci. 1994, 14, 5011–5027. [Google Scholar]
  205. Lalo, U.V.; Pankratov, Y.V.; Arndts, D.; Krishtal, O.A. Omega-conotoxin GVIA potently inhibits the currents mediated by P2X receptors in rat DRG neurons. Brain. Res. Bull. 2001, 54, 507–512. [Google Scholar]
  206. Skals, M.; Jorgensen, N.R.; Leipziger, J.; Praetorius, H.A. Alpha-hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis. Proc. Natl. Acad. Sci. USA 2009, 106, 4030–4035. [Google Scholar]
  207. Yilmaz, O.; Yao, L.; Maeda, K.; Rose, T.M.; Lewis, E.L.; Duman, M.; Lamont, R.J.; Ojcius, D.M. ATP scavenging by the intracellular pathogen Porphyromonas gingivalis inhibits P2X7-mediated host-cell apoptosis. Cell Microbiol. 2008, 10, 863–875. [Google Scholar]
  208. Csolle, C.; Sperlagh, B. Peripheral origin of IL-1beta production in the rodent hippocampus under in vivo systemic bacterial lipopolysaccharide (LPS) challenge and its regulation by P2X(7) receptors. J. Neuroimmunol. 2010, 219, 38–46. [Google Scholar] [CrossRef] [PubMed]
  209. Verstrepen, L.; Bekaert, T.; Chau, T.L.; Tavernier, J.; Chariot, A.; Beyaert, R. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: Variations on a common theme. Cell Mol. Life. Sci. 2008, 65, 2964–2978. [Google Scholar]
  210. Cameron, D.J. Inhibition of macrophage mediated cytotoxicity by exogenous adenosine. 5'-triphosphate. J. Clin. Lab. Immunol. 1984, 15, 215–218. [Google Scholar] [PubMed]
  211. Schilling, W.P.; Wasylyna, T.; Dubyak, G.R.; Humphreys, B.D.; Sinkins, W.G. Maitotoxin and P2Z/P2X(7) purinergic receptor stimulation activate a common cytolytic pore. Am. J. Physiol. 1999, 277, C766–776. [Google Scholar]
  212. Lundy, P.M.; Nelson, P.; Mi, L.; Frew, R.; Minaker, S.; Vair, C.; Sawyer, T.W. Pharmacological differentiation of the P2X7 receptor and the maitotoxin-activated cationic channel. Eur. J. Pharmacol. 2004, 487, 17–28. [Google Scholar]

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Nasiripourdori, A.; Taly, V.; Grutter, T.; Taly, A. From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules. Toxins 2011, 3, 260-293. https://doi.org/10.3390/toxins3030260

AMA Style

Nasiripourdori A, Taly V, Grutter T, Taly A. From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules. Toxins. 2011; 3(3):260-293. https://doi.org/10.3390/toxins3030260

Chicago/Turabian Style

Nasiripourdori, Adak, Valérie Taly, Thomas Grutter, and Antoine Taly. 2011. "From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules" Toxins 3, no. 3: 260-293. https://doi.org/10.3390/toxins3030260

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