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{{Orphan|date=October 2014}} |
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| ⚫ | '''BotIT2''' is a [[neurotoxin]] |
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== Source and etymology == |
== Source and etymology == |
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BotIT2 is found in the venom of the scorpion ''Buthus occitanus tunetanus'' (Bot) <ref name=Borchani /> and hence named Buthus occitanus tunetanus insect toxin 2 (BotIT2).<ref name=Uniprot /> |
BotIT2 is found in the venom of the scorpion ''[[Buthus occitanus]] tunetanus'' (Bot) <ref name=Borchani /> and hence named Buthus occitanus tunetanus insect toxin 2 (BotIT2).<ref name=Uniprot /> |
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== Chemistry == |
== Chemistry == |
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Classification of toxins is based on their structural, antigenic and pharmacological properties.<ref name=Mejri /> |
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=== Structure === |
=== Structure === |
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|N'—DGYIKGYKGCKITCVINDDYCDTECKAEGGTYGICWKWGLACWCEDLPEDKRWKPETNTC –C' |
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|N’—DGYIKGYKGCKITCVINDDYCDTECKAEGGTYGICWKWGLACWCEDLPEDKRWKPETNTC –C’ |
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|'''Fig.1 Amino acid sequence of BotIT2 including [[N-terminus]] and [[C-terminus]].<ref name=Borchani/><ref name=Uniprot />''' |
|'''Fig.1 Amino acid sequence of BotIT2 including [[N-terminus]] and [[C-terminus]].<ref name=Borchani/><ref name=Uniprot />''' |
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=== Homology === |
=== Homology === |
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BotIT2 differs from other scorpion toxins not only in its amino acid sequence, but in its effects on activation kinetics of insect [[sodium channel]]s as well. Similarities are found between BotIT2 and other [[neurotoxin]]s. For example, the degree of similarity with the α-type and β-type toxins, flaccid-depressive insect toxins and BotIT4 is 30-40%, 60-70%,<ref name=Cestele /> and 67%,<ref name=Borchani /> respectively. |
BotIT2 differs from other scorpion toxins not only in its amino acid sequence, but in its effects on activation kinetics of insect [[sodium channel]]s as well. Similarities are found between BotIT2 and other [[neurotoxin]]s. For example, the degree of similarity with the α-type and β-type toxins, flaccid-depressive insect toxins and BotIT4 is 30-40%, 60-70%,<ref name=Cestele /> and 67%,<ref name=Borchani /> respectively. |
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Despite |
Despite 67% homogeneity with BotIT4, BotIT4 can be discriminated from BotIT2, by binding two [[sodium channel]] sites and having its exclusive depressant electrophysiological function. However, BotIT4 and BotIT2 do share binding characteristics.<ref name=Cestele /><ref name=Borchani2 /> |
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== Target == |
== Target == |
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BotIT2 binds site 4 of voltage gated sodium channels with low capacity (Bmax = 2.4 ± 0.5 pmol/mg) and high affinity (Kd = 0.3 ± 0.1 nM).<ref name=Cestele /> Besides its influence in insects, BotIT2 affects neuronal membrane properties of mammals as well, but in a less potent way (see [[#Toxicity|Toxicity]]).<ref name=Borchani3 /> |
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== Mode of action == |
== Mode of action == |
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The effect of BotIT2 was investigated in the giant axon |
The effect of BotIT2 was investigated in the giant axon and dorsal unpaired median (DUM) neurons of the [[American cockroach]] (''Periplaneta americana''), to examine its influence on neuronal excitability by means of [[voltage clamp]] and [[current clamp]] recordings.<ref name=Borchani /><ref name=Stankiewicz /> |
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Application of BotIT2 transforms the fast sodium current into a slow sodium current.<ref name=Cestele /><ref name=Borchani /> The difference in [[ |
Application of BotIT2 transforms the fast sodium current into a slow sodium current.<ref name=Cestele /><ref name=Borchani /> The difference in [[gating (electrophysiology)|gating]] modes from fast to slow are caused by changes in structural conformation. The voltage dependence of this slow current does not differ from the dependence of the fast current. However, the kinetics (activation and deactivation) of the current are slowed down by 40-300 times.<ref name=Stankiewicz /> |
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This slow sodium current induces [[depolarization]] and results in repetitive firing pattern and burst firing in a time-dependent manner. BotIT2 decreases the maximal peak of the fast depolarizing sodium inward current and thus causes a decrease in [[action potential]] amplitude.<ref name=Borchani /><ref name=Stankiewicz /> <br /> |
This slow sodium current induces a [[depolarization]] and results in repetitive firing pattern and burst firing in a time-dependent manner. BotIT2 decreases the maximal peak of the fast depolarizing sodium inward current and thus causes a decrease in [[action potential]] amplitude.<ref name=Borchani /><ref name=Stankiewicz /> <br /> |
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Together, BotIT2 modifies the kinetics of |
Together, BotIT2 modifies the kinetics of insect's [[sodium channel]] activation, transforms fast sodium currents in slow current and enhances (in DUM) or induces (in the axon) a repetitive firing pattern or burst activity, but of smaller amplitude. |
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== Toxicity == |
== Toxicity == |
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BotIT2 is highly toxic in insects.<ref name=Cestele /><ref name=Borchani /><ref name=Mejri /><ref name=Stankiewicz /> For instance, injection of BotIT2 into the [[German cockroach]] (''Blatella Germanica'') results in a contraction paralysis effect.<ref name=Cestele /><ref name=Stankiewicz /> Although the toxin induces neurotoxic symptoms in mice too, it is less potent in mammals than in insects<ref name=Cestele /><ref name=Borchani /> ([[LD50]] in mice = 1 |
BotIT2 is highly toxic in insects.<ref name=Cestele /><ref name=Borchani /><ref name=Mejri /><ref name=Stankiewicz /> For instance, injection of BotIT2 into the [[German cockroach]] (''Blatella Germanica'') results in a contraction paralysis effect.<ref name=Cestele /><ref name=Stankiewicz /> Although the toxin induces neurotoxic symptoms in mice too, it is less potent in mammals than in insects<ref name=Cestele /><ref name=Borchani /> ([[LD50]] in mice = 1 μg/20 g; [[LD50]] in ''B. Germanica'' = 135 ng/100 mg<ref name=Cestele /><ref name=Stankiewicz />). |
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So far, the underlying mechanism of the toxic behavior has not been fully understood. High toxicity of the toxins in animals could be explained by the presence of different toxins in the venom of the Buthus occitanus tunetanus (BotIT1, BotIT4 and BotIT5) which acts collectively to insects. Another possibility might be a cooperative interaction between the toxins in the venom. In general, [[scorpion toxin]]s bind to ion channels via sites of positive surface potential. The total positive charge of the toxin increases its [[toxicity]]. Table 1 indicates whole charge for some Bot insect toxins and their toxicity. BotIT2 its whole charge is negative (-3), like BotIT4/5 (-2), whereas it is positive for BotIT6 (+3).<ref name=Mejri /> Therefore, BotIT2 is the least potent ([[LD50]]= 135)<ref name=Borchani /><ref name=Mejri /> when compared to BotIT4, BotIT5 and BotIT64.<ref name=Mejri /> |
So far, the underlying mechanism of the toxic behavior has not been fully understood. High toxicity of the toxins in animals could be explained by the presence of different toxins in the venom of the Buthus occitanus tunetanus (BotIT1, BotIT4 and BotIT5) which acts collectively to insects. Another possibility might be a cooperative interaction between the toxins in the venom. In general, [[scorpion toxin]]s bind to ion channels via sites of positive surface potential. The total positive charge of the toxin increases its [[toxicity]]. Table 1 indicates whole charge for some Bot insect toxins and their toxicity. BotIT2 its whole charge is negative (-3), like BotIT4/5 (-2), whereas it is positive for BotIT6 (+3).<ref name=Mejri /> Therefore, BotIT2 is the least potent ([[LD50]]= 135)<ref name=Borchani /><ref name=Mejri /> when compared to BotIT4, BotIT5 and BotIT64.<ref name=Mejri /> |
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== Treatment == |
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Until recently, no treatment options for exposure to BotIT2 are known yet. |
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== Application == |
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So far, BotIT2 is not used for therapeutic purposes. Since BotIT2 is also considered as an depressant insect toxin, like BotIT6, it might be also an appropriate toxin for the construction of novel recombinant [[baculovirus]], which might be used in therapeutic cancer vaccins. |
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Also, this toxin represents a novel interesting tool to elucidate structure-function relations of [[scorpion toxin]]s.<ref name=Mejri /> This could allow better understanding about mechanisms of neuronal excitation in insects.<ref name=Mejri /><ref name=Stankiewicz /> |
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== References == |
== References == |
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{{Reflist|refs= |
{{Reflist|30em|refs= |
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<ref name=Cestele>Cestèle |
<ref name=Cestele>{{cite journal |last1=Cestèle |first1=Sandrine |last2=Borchani |first2=Lamia |last3=El Ayeb |first3=Mohamed |last4=Rochat |year=1997 |first4=Hervé |title=Bot IT2: A new scorpion toxin to study receptor site on insect sodium channels |journal=FEBS Letters |volume=405 |issue=1 |pages=77–80 |pmid=9094428 |doi=10.1016/S0014-5793(97)00160-9|doi-access=free }}</ref> |
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<ref name=Borchani>Borchani |
<ref name=Borchani>{{cite journal |last1=Borchani |first1=Lamia |last2=Mansuelle |first2=Pascal |last3=Stankiewicz |first3=Maria |last4=Grolleau |first4=Francoise |last5=Cestele |first5=Sandrine |last6=Karoui |first6=Habib |last7=Lapied |first7=Bruno |last8=Rochat |first8=Herve |last9=Pelhate |first9=Marcel |last10=Ayeb |first10=Mohamed |year=1996 |title=A New Scorpion Venom Toxin Paralytic to Insects that Affects Na+ Channel Activation |journal=European Journal of Biochemistry |volume=241 |issue=2 |pages=525–32 |pmid=8917451 |doi=10.1111/j.1432-1033.1996.00525.x|doi-access=free }}</ref> |
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<ref name=Uniprot>Uniprot |
<ref name=Uniprot>{{cite web |publisher=Uniprot |title=Beta-insect depressant toxin BotIT6 |url=https://www.uniprot.org/uniprot/P59864 |date=October 1, 2014}}</ref> |
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<ref name=Mejri>Mejri |
<ref name=Mejri>{{cite journal |last1=Mejri |first1=Thouraya |last2=Borchani |first2=Lamia |last3=Srairi-Abid |first3=Najet |last4=Benkhalifa |first4=Rym |last5=Cestele |first5=Sandrine |last6=Regaya |first6=Imed |last7=Karoui |first7=Habib |last8=Pelhate |first8=Marcel |last9=Rochat |first9=Hervé |last10=El Ayeb |first10=Mohamed |year=2003 |title=BotIT6: A potent depressant insect toxin from Buthus occitanus tunetanus venom |journal=Toxicon |volume=41 |issue=2 |pages=163–71 |pmid=12565735 |doi=10.1016/S0041-0101(02)00246-5}}</ref> |
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<ref name=Jover>Jover |
<ref name=Jover>{{cite journal |last1=Jover |first1=Emmanuel |last2=Couraud |first2=François |last3=Rochat |first3=Hervé |year=1980 |title=Two types of scorpion neurotoxins characterized by their binding to two separate receptor sites on rat brain synaptosomes |journal=Biochemical and Biophysical Research Communications |volume=95 |issue=4 |pages=1607–14 |pmid=7417336 |doi=10.1016/S0006-291X(80)80082-9}}</ref> |
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<ref name= cestele2> |
<ref name= cestele2>{{cite journal |last1=Cestele |first1=Sandrine |last2=Kopeyan |first2=Charles |last3=Oughideni |first3=Razika |last4=Mansuelle |first4=Pascal |last5=Granier |first5=Claude |last6=Rochat |first6=Herve |year=1997 |title=Biochemical and Pharmacological Characterization of a Depressant Insect Toxin from the Venom of the Scorpion Buthacus arenicola |journal=European Journal of Biochemistry |volume=243 |issue=1–2 |pages=93–9 |pmid=9030726 |doi=10.1111/j.1432-1033.1997.93_1a.x|doi-access=free }}</ref> |
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<ref name=Borchani2>Borchani |
<ref name=Borchani2>{{cite journal |last1=Borchani |first1=Lamia |last2=Stankiewicz |first2=Maria |last3=Kopeyan |first3=Charles |last4=Mansuelle |first4=Pascal |last5=Kharrat |first5=Riadh |last6=Cestèle |first6=Sandrine |last7=Karoui |first7=Habib |last8=Rochat |first8=Hervé |last9=Pelhate |first9=Marcel |last10=El Ayeb |first10=Mohamed |year=1997 |title=Purification, structure and activity of three insect toxins from Buthus occitanus tunetanus venom |journal=Toxicon |volume=35 |issue=3 |pages=365–82 |pmid=9080593 |doi=10.1016/S0041-0101(96)00173-0}}</ref> |
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| ⚫ | <ref name=Stankiewicz>{{cite journal |last1=Stankiewicz |first1=M. |last2=Grolleau |first2=F. |last3=Lapied |first3=B. |last4=Borchani |first4=L. |last5=El Ayeb |first5=M. |last6=Pelhate |first6=M. |year=1996 |title=Bot IT2, a toxin paralytic to insects from the Buthus occitanus tunetanus venom modifying the activity of insect sodium channels |journal=Journal of Insect Physiology |volume=42 |issue=4 |pages=397–405 |doi=10.1016/0022-1910(95)00120-4}}</ref> |
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<ref name=Catterall>Catterall. Voltage-gated ion channels and gating modifier toxins. [http://www.ncbi.nlm.nih.gov/pubmed/17239913 PMID 17239913]</ref> |
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<ref name=Borchani3>{{cite journal |last1=Borchani |first1=L. |last2=Kharrat |first2=R. |last3=Karoui |first3=H. |last4=Dellagi |first4=K. |last5=Ayeb |first5=M.El |last6=Stankiewicz |first6=M. |last7=Grolleau |first7=F. |last8=Lapied |first8=B. |last9=Pelhate |first9=M. |last10=Mansuelle |first10=P. |last11=Cestele |first11=S. |last12=Rochat |first12=H. |year=1995 |title=Purification and characterization of insect toxins from the venom of the scorpion Buthus occitanus tunetanus |journal=Toxicon |volume=33 |issue=9 |pages=1120 |doi=10.1016/0041-0101(95)93831-E}}</ref> |
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| ⚫ | <ref name=Stankiewicz>Stankiewicz |
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<ref name=Borchani3>Borchani L., Kharrat R., Karoui H., Dellagi K., El Ayeb M., Stankiewicz M., Grolleau F., Lapied B., Pelhate M., Mansuelle P., Cestele S. and Rochat H. (1995) Purification and characterization of a protein belonging to a new class of toxins active on insects. Toxicon 33, 1120. [http://www.sciencedirect.com/science/article/pii/004101019593831E DOI: 10.1016/0041-0101(95)93831-E]</ref> |
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}} |
}} |
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Latest revision as of 19:37, 10 June 2024
BotIT2 is a neurotoxin from the scorpion Buthus occitanus tunetanus, which modifies activation and slows down the deactivation of voltage gated sodium channels. [1]
Source and etymology
[edit]BotIT2 is found in the venom of the scorpion Buthus occitanus tunetanus (Bot) [2] and hence named Buthus occitanus tunetanus insect toxin 2 (BotIT2).[3]
Chemistry
[edit]Structure
[edit]| N'—DGYIKGYKGCKITCVINDDYCDTECKAEGGTYGICWKWGLACWCEDLPEDKRWKPETNTC –C' |
| Fig.1 Amino acid sequence of BotIT2 including N-terminus and C-terminus.[2][3] |
The BotIT2 peptide is composed of 60 amino-acids (Fig. 1) and its C-terminal residue contains a free carboxyl group. The molecular mass of BotIT2 is 6919 Da.[2][3]
Family
[edit]BotIT2 belongs to the Buthidae neurotoxin family. Three main groups are distinguishable in this family: the α-, the β- and the depressant toxins.[4] The BotIT2 has characteristics of all these subgroups.[5] However, BotIT2 is classified as a β-depressant toxin.[3]
Homology
[edit]BotIT2 differs from other scorpion toxins not only in its amino acid sequence, but in its effects on activation kinetics of insect sodium channels as well. Similarities are found between BotIT2 and other neurotoxins. For example, the degree of similarity with the α-type and β-type toxins, flaccid-depressive insect toxins and BotIT4 is 30-40%, 60-70%,[1] and 67%,[2] respectively. Despite 67% homogeneity with BotIT4, BotIT4 can be discriminated from BotIT2, by binding two sodium channel sites and having its exclusive depressant electrophysiological function. However, BotIT4 and BotIT2 do share binding characteristics.[1][6]
Target
[edit]BotIT2 binds site 4 of voltage gated sodium channels with low capacity (Bmax = 2.4 ± 0.5 pmol/mg) and high affinity (Kd = 0.3 ± 0.1 nM).[1] Besides its influence in insects, BotIT2 affects neuronal membrane properties of mammals as well, but in a less potent way (see Toxicity).[7]
Mode of action
[edit]The effect of BotIT2 was investigated in the giant axon and dorsal unpaired median (DUM) neurons of the American cockroach (Periplaneta americana), to examine its influence on neuronal excitability by means of voltage clamp and current clamp recordings.[2][8]
Application of BotIT2 transforms the fast sodium current into a slow sodium current.[1][2] The difference in gating modes from fast to slow are caused by changes in structural conformation. The voltage dependence of this slow current does not differ from the dependence of the fast current. However, the kinetics (activation and deactivation) of the current are slowed down by 40-300 times.[8]
This slow sodium current induces a depolarization and results in repetitive firing pattern and burst firing in a time-dependent manner. BotIT2 decreases the maximal peak of the fast depolarizing sodium inward current and thus causes a decrease in action potential amplitude.[2][8]
Together, BotIT2 modifies the kinetics of insect's sodium channel activation, transforms fast sodium currents in slow current and enhances (in DUM) or induces (in the axon) a repetitive firing pattern or burst activity, but of smaller amplitude.
Toxicity
[edit]| Table 1. Whole charge and toxicity (LD50) of Bot insect toxins in B. Germanica.[2][9] | ||
| Insect toxin | Whole charge | Toxicity (ng/100 body weight) |
|---|---|---|
| BotIT6 |
+3 |
10 |
| BotIT4/IT5 |
-2 |
110 |
| BotIT3 |
-3 |
135 |
BotIT2 is highly toxic in insects.[1][2][9][8] For instance, injection of BotIT2 into the German cockroach (Blatella Germanica) results in a contraction paralysis effect.[1][8] Although the toxin induces neurotoxic symptoms in mice too, it is less potent in mammals than in insects[1][2] (LD50 in mice = 1 μg/20 g; LD50 in B. Germanica = 135 ng/100 mg[1][8]). So far, the underlying mechanism of the toxic behavior has not been fully understood. High toxicity of the toxins in animals could be explained by the presence of different toxins in the venom of the Buthus occitanus tunetanus (BotIT1, BotIT4 and BotIT5) which acts collectively to insects. Another possibility might be a cooperative interaction between the toxins in the venom. In general, scorpion toxins bind to ion channels via sites of positive surface potential. The total positive charge of the toxin increases its toxicity. Table 1 indicates whole charge for some Bot insect toxins and their toxicity. BotIT2 its whole charge is negative (-3), like BotIT4/5 (-2), whereas it is positive for BotIT6 (+3).[9] Therefore, BotIT2 is the least potent (LD50= 135)[2][9] when compared to BotIT4, BotIT5 and BotIT64.[9]
References
[edit]- ^ a b c d e f g h i Cestèle, Sandrine; Borchani, Lamia; El Ayeb, Mohamed; Rochat, Hervé (1997). "Bot IT2: A new scorpion toxin to study receptor site on insect sodium channels". FEBS Letters. 405 (1): 77–80. doi:10.1016/S0014-5793(97)00160-9. PMID 9094428.
- ^ a b c d e f g h i j k Borchani, Lamia; Mansuelle, Pascal; Stankiewicz, Maria; Grolleau, Francoise; Cestele, Sandrine; Karoui, Habib; Lapied, Bruno; Rochat, Herve; Pelhate, Marcel; Ayeb, Mohamed (1996). "A New Scorpion Venom Toxin Paralytic to Insects that Affects Na+ Channel Activation". European Journal of Biochemistry. 241 (2): 525–32. doi:10.1111/j.1432-1033.1996.00525.x. PMID 8917451.
- ^ a b c d "Beta-insect depressant toxin BotIT6". Uniprot. October 1, 2014.
- ^ Jover, Emmanuel; Couraud, François; Rochat, Hervé (1980). "Two types of scorpion neurotoxins characterized by their binding to two separate receptor sites on rat brain synaptosomes". Biochemical and Biophysical Research Communications. 95 (4): 1607–14. doi:10.1016/S0006-291X(80)80082-9. PMID 7417336.
- ^ Cestele, Sandrine; Kopeyan, Charles; Oughideni, Razika; Mansuelle, Pascal; Granier, Claude; Rochat, Herve (1997). "Biochemical and Pharmacological Characterization of a Depressant Insect Toxin from the Venom of the Scorpion Buthacus arenicola". European Journal of Biochemistry. 243 (1–2): 93–9. doi:10.1111/j.1432-1033.1997.93_1a.x. PMID 9030726.
- ^ Borchani, Lamia; Stankiewicz, Maria; Kopeyan, Charles; Mansuelle, Pascal; Kharrat, Riadh; Cestèle, Sandrine; Karoui, Habib; Rochat, Hervé; Pelhate, Marcel; El Ayeb, Mohamed (1997). "Purification, structure and activity of three insect toxins from Buthus occitanus tunetanus venom". Toxicon. 35 (3): 365–82. doi:10.1016/S0041-0101(96)00173-0. PMID 9080593.
- ^ Borchani, L.; Kharrat, R.; Karoui, H.; Dellagi, K.; Ayeb, M.El; Stankiewicz, M.; Grolleau, F.; Lapied, B.; Pelhate, M.; Mansuelle, P.; Cestele, S.; Rochat, H. (1995). "Purification and characterization of insect toxins from the venom of the scorpion Buthus occitanus tunetanus". Toxicon. 33 (9): 1120. doi:10.1016/0041-0101(95)93831-E.
- ^ a b c d e f Stankiewicz, M.; Grolleau, F.; Lapied, B.; Borchani, L.; El Ayeb, M.; Pelhate, M. (1996). "Bot IT2, a toxin paralytic to insects from the Buthus occitanus tunetanus venom modifying the activity of insect sodium channels". Journal of Insect Physiology. 42 (4): 397–405. doi:10.1016/0022-1910(95)00120-4.
- ^ a b c d e Mejri, Thouraya; Borchani, Lamia; Srairi-Abid, Najet; Benkhalifa, Rym; Cestele, Sandrine; Regaya, Imed; Karoui, Habib; Pelhate, Marcel; Rochat, Hervé; El Ayeb, Mohamed (2003). "BotIT6: A potent depressant insect toxin from Buthus occitanus tunetanus venom". Toxicon. 41 (2): 163–71. doi:10.1016/S0041-0101(02)00246-5. PMID 12565735.