Av3
| Molecular formula | C125H171N35O36S6 |
|---|---|
| Number of atoms | 202 |
| Molecular mass | 2.94 kDa |
| pI | 8.1 |
| Amino acid sequence (27 residues) | R S C C P C Y W G G C P W G Q N C Y P E G S C G P K V |
| Modifications | Disulfide bonds: 3-17, 4-11, 6-22 |
Av3
Av3 (also: ATX III, Delta-actitoxin-Avd2a, Delta-AITX-AVd2a, neurotoxin 3) is a 27-residue polypeptide neurotoxin produced by Anemonia viridis (also Anemonia sulcata'). Av3 binds to sodium channels, resulting in the slowing or reduction of channel inactivation which ultimately prolongs the action potential in excitable tissues.
Etymology
Av3 is an abbreviation from Anemonia Viridis toxin 3. Originally Av3 was called ATX-III, which is an acronym for Anemonia Sulcata toxin 3. In recent literature, researchers use the species name Anemonia viridis as a synonym for Anemonia sulcata,[1][2][3], but this is not correct as Anemonia viridis and Anemonia sulcata are two different species.[4]
Source
Av3 is isolated from the venom of the sea anemones Anemonia viridis and Anemonia sulcata. Av3 was the third toxin isolated from the venom of Anemonia sulcata, the first and second being ATX-I and ATX-II.[5][2]
Chemistry
Av3 is a small neurotoxin consisting of 27 amino acids stabilized by three disulfide bridges.[2] The polypeptide contains no regular a-helix or f-sheet and instead consists of a network of reverse turns.[6] The molecule can be divided into three regions: a polar N-terminal dipeptide, a predominantly hydrophobic central region (residues 3-14), and a polar C-terminal segment.[7]
Av3 is structurally unique compared to bioactive surfaces of toxins with a similar target and consists mainly of aromatic residues as well as glycine residues. Glycine residues make up nearly 20% of the total amino acid content.[2][7]
Target
Av3 acts on voltage-gated sodium channels (Nav) by inhibiting fast inactivation, thereby prolonging the sodium-dependent action potential.[8] Specifically, Av3 binds to a cleft in S6 of domain I [1] and likely also has contact with the S4 region of domain IV, which is proximal to the pore module of Domain I.[3]
Two studies compared the effect of Av3 between insect sodium channels and mammalian channels. These studies found that while an effect of Av3 was found on insect sodium channels, no such effect could be found on mammalian sodium channels [1][2] One study tested the effect of 10 µM Av3 on four mammalian Nav subtypes: rNav1.2, rNav1.4, hNav1.4 and rNav1.6, and found only a ‘negligible effect’ on mammalian subtype hNav1.5 while no effect on the other mammalian Nav subtypes was found.[2] Another study also found that 10 µM Av3 had no effect on the rNav1.2a channel, while the toxin did inhibit Drosophila melanogaster DmNav1 inactivation.[1] A similar effect on sodium channel activity was also found for crayfish neurones.[8]
Competition binding assays demonstrate that Av3 competes with the scorpion α-toxin LqhαIT, which is known to bind site-3 on the extracellular region of the α-subunit of insect Navs, confirming the classification of Av3 as a site-3 toxin.[2]
Mode of action
Av3 selectively targets voltage-gated sodium channels (Nav) on the extracellular region of the α-subunit.[9] Through this interaction, the toxin functions as a gating modifier that inhibits the fast inactivation, increases peak sodium current at more negative membrane potentials, and shifts activation to lower voltages, resulting in a sustained inward sodium current and prolonged action potentials.[8]
The binding of Av3 is voltage dependent: depolarizing the membrane increases the toxin's dissociation rate from the channel, indicating stronger interactions with sodium channels in their resting and early open states than when they are strongly activated.[10] For example, the dissociation rate increases by approximately two orders of magnitude when the membrane potential is shifted from –100 mV to 0 mV.[10]
In crayfish neurons, it was found that Av3 shifts the voltage dependence of activation to more negative potentials, causing voltage channels to open earlier and neurons to become hyperexcitable.[8]
These combined effects initially lead to repetitive firing, but as depolarization persists and sodium channels fail to recover, action potential propagation is disrupted, consistent with the paralysis observed in crustaceans.[5][8]
Toxicity
Av3 produces neurotoxic symptoms in crustaceans, typically causing cramp-like reactions followed by paralysis of the extremities when injected into Carcinus maenas.[5] The toxicity reflects the toxin’s high selectivity for invertebrate sodium channels, with minimal effects on vertebrate channels at comparable concentrations.[1][2] Although the symptoms in arthropods are well described, quantitative LD50 data have not been reported. In contrast, i.p. LD50 in mice is greater than 18 mg/kg, indicating low toxicity in mammals.[11]
Treatment
Based on available literature, no specific antivenom or therapeutic treatment for AV3 has been reported.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Gur Barzilai, Maya; Kahn, Roy; Regev, Noa; Gordon, Dalia; Moran, Yehu; Gurevitz, Michael (2014-10-15). "The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2–S6 in the pore module of target sodium channels". Biochemical Journal. 463 (2): 271–277. doi:10.1042/BJ20140576. ISSN 0264-6021. PMID 25055135.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Moran, Yehu; Kahn, Roy; Cohen, Lior; Gur, Maya; Karbat, Izhar; Gordon, Dalia; Gurevitz, Michael (2007-08-15). "Molecular analysis of the sea anemone toxin Av3 reveals selectivity to insects and demonstrates the heterogeneity of receptor site-3 on voltage-gated Na+ channels". Biochemical Journal. 406 (1): 41–48. doi:10.1042/BJ20070233. ISSN 0264-6021. PMC 1948988. PMID 17492942.
- ↑ 3.0 3.1 Zhu, Qing; Du, Yuzhe; Nomura, Yoshiko; Gao, Rong; Cang, Zixuan; Wei, Guo-Wei; Gordon, Dalia; Gurevitz, Michael; Groome, James; Dong, Ke (2021-10-01). "Charge substitutions at the voltage-sensing module of domain III enhance actions of site-3 and site-4 toxins on an insect sodium channel". Insect Biochemistry and Molecular Biology. 137. Bibcode:2021IBMB..13703625Z. doi:10.1016/j.ibmb.2021.103625. ISSN 0965-1748. PMC 9376739 Check
|pmc=value (help). PMID 34358664 Check|pmid=value (help). Unknown parameter|article-number=ignored (help) - ↑ "Anemonia sulcata, Snakelocks anemone". www.sealifebase.ca. Retrieved 2025-11-12.
- ↑ 5.0 5.1 5.2 Be´Ress, La´Szlo; Be´Ress, Rosemarie (1975). "Isolation and characterisation of three polypeptides with neurotoxic activity fromAnemonia sulcata". FEBS Letters. 50 (3): 311–314. Bibcode:1975FEBSL..50..311B. doi:10.1016/0014-5793(75)90057-5. ISSN 1873-3468.
- ↑ Norton, R S; Cross, K; Braach-Maksvytis; Wachter, E (1993-07-15). "1H-n.m.r. study of the solution properties and secondary structure of neurotoxin III from the sea anemone Anemonia sulcata". Biochemical Journal. 293 (2): 545–551. Bibcode:1975FEBSL..50..311B. doi:10.1042/BJ20070233. ISSN 0264-6021. PMID 2409523. Text "first3" ignored (help); Text "V " ignored (help)
- ↑ 7.0 7.1 Martinez, G.; Kopeyan, C. (1977). "Toxin III from Anemonia sulcata: Primary structure". FEBS Letters. 84 (2): 247–252. Bibcode:1977FEBSL..84..247M. doi:10.1016/0014-5793(77)80699-6. ISSN 1873-3468. PMID 2451216.
- ↑ 8.0 8.1 8.2 8.3 8.4 Hartung, Klaus; Rathmayer, Werner (1985-05-01). "Anemonia sulcata toxins modify activation and inactivation of Na+ currents in a crayfish giant axons". Pflügers Archiv. 411 (1): 88–93. Bibcode:1985Pfluec..411..088H Check
|bibcode=length (help). doi:10.1007/BF00581651. ISSN 1432-2013. PMID 2451216. - ↑ Catterall, William A.; Cestèle, Sandrine; Yarov-Yarovoy, Vladimir; Yu, Frank H.; Konoki, Keiichi; Scheuer, Todd (February 2007). "Voltage-gated ion channels and gating modifier toxins". Toxicon. 49 (2): 124–141. Bibcode:2007Txcn...49..124C. doi:10.1016/j.toxicon.2006.09.022. ISSN 0041-0101. PMID 17239913.
- ↑ 10.0 10.1 Warashina, Akira; Jiang, Zheng-Yao; Ogura, Tatsuya (1988-01-01). "Potential-dependent action ofAnemonia sulcata toxins III and IV on sodium channels in crayfish giant axons". Pflügers Archiv. 411 (1): 88–93. Bibcode:1988Pfluec..411..088W Check
|bibcode=length (help). doi:10.1007/BF00581651. ISSN 1432-2013. PMID 2451216. - ↑ Schweitz, Hugues (1984-01-01). "Lethal potency in mice of toxins from scorpion, sea anemone, snake and bee venoms following intraperitoneal and intracisternal injection". Toxicon. 22 (2): 308–311. Bibcode:1984Txcn...22..308S. doi:10.1016/0041-0101(84)90032-1. ISSN 0041-0101. PMID 6145236.
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