RTX-III (neurotoxin-III) is a peptide neurotoxin derived from the sea anemone Radianthus macrodactylus. The toxin targets voltage-dependent sodium channels by preventing its complete inactivation, which can lead to a prolonged influx of sodium ions and depolarization of the cell’s membrane.
Source
editRTX-III is secreted by the sea anemone Radianthus macrodactylus, also known as Heteractis crispa, which inhabits the Indian and Pacific Oceans.[2]
Structure
editPrimary structure
editThe RTX-III neuropeptide consists of 48 amino acids cross-linked by three disulfide linkages.[3]
The amino acid sequence of the neurotoxin-III is:
- GNCKCDDEGPYVRTAPLTGYVDLGYCNEGWEKCASYYSPIAECCRKKK[3]
and its molecular mass is 5378.33 Da.[3]
Secondary structure
editDue to RTX-III's structural characteristics, this toxin is categorized as a type II sea anemone neurotoxin. The toxin has a guanidine group of Arg13 residues,[2] as well as disulfide bridges which may be important in maintaining its active conformation.[5]
Homology
editRTX-III is highly homologous with ShI, also a type II toxin from the sea anemone Stichodactyla helianthus, where their sequences share 88% of identity.[3][6][7] RTX-III also shares significant homology with other toxins in the type II family, including RpII and RTX-VI.[8]
Target
editRTX-III is a Nav activator (also known as a sodium channel opener), which elicits changes in the functioning voltage-gated sodium channels of arthropods, insects and mammals. Research has shown evidence of affinity binding with various types of sodium channels.[8] The toxin modulates the BgNav1 subtype of insects and the VdNav1 subtype of arachnoids. In mammals, it selectively affects the central nervous system, modulating Nav1.1, Nav1.2 and Nav 1.3, as well as the Nav1.6 subtype.[8]
All sea anemone toxins are thought to bind within binding site 3 of voltage-dependent sodium channels. The binding site for RTX-III, in particular, is proposed to overlap with that of the channel-inactivating scorpion α-toxins and spider δ-toxins, though it is not entirely identical.[8]
Mode of action
editRTX-III prevents or reduces the speed with which sodium channels are inactivated. The toxin inhibits the inactivation of the voltage-dependent sodium channels in a selective manner. The sodium channels may stay open for longer than normal, and consequently, the influx of sodium is prolonged.[2] In turn, the influx of sodium may depolarize the membrane potential value towards a more positive membrane potential. Therefore, inactivation will be incomplete and less sensitive to any potential changes, slowing down the kinetics of sodium inactivation.[8]
RTX-III defers from the conventional way in which sea anemones operate – an arginine residue being the center of binding with a sodium channel.[2] In the case of neurotoxin-III, it is hypothesized that Arg13 may play a role in selecting specific sodium channel isoforms.[2][9][10] However, these findings might only partially apply to RTX-III since a different, homologous toxin was investigated – RTX-VI.[9][10]
Toxicity and potency
editRTX-III presents a high toxicity in mammals. The LD₅₀ for mice varies from 25 to 40 µg/kg, while the LD100 is 82 µg/kg in arthropods.[3] Specific amino acid substitutions in the RTX-III sequence occur at the positions most toxic for mice.[3]
The EC50 values of RTX-III also differ between mammals (381.8 nM) and insects/arthropods (978.1 nM).[8] RTX-III displays a higher potency in arachnid and insect channels, with high EC50 values. However, in mammalian channels the toxin may be less potent, showing low EC50 values.[8] Since RTX-III is produced by a sea anemone, its main role is the effective modulation of arthropod sodium channels, so that the prey is immobilized but not necessarily killed.[8]
| LD50 (µg/kg) | LD100(µg/kg) | EC50 (nM) | |
|---|---|---|---|
| Mammals | 25-40 | x | 381.8 |
| Insects / Arthropods | x | 82 | 978.1 |
RTX-III’s toxic properties are distributed between its many functional groups, such as the Arg-13 guanidine group[11] and the Gly-1 amino group.[2]
Treatment and therapeutic uses
editCurrent research has not reached any significant conclusions regarding the treatment or therapeutic use of RTX-III.
References
edit- ^ Karelj (2011-07-29), English: Sea anemone Sebae anemone, (Heteractis crispa) in Prague sea aquarium "Sea world", Czech Republic, retrieved 2024-10-23
- ^ a b c d e f Mahnir, Vladimir M.; Kozlovskaya, Emma P. (1991-01-01). "Structure-toxicity relationships of neurotoxin RTX-III from the sea anemone Radianthus macrodactylus: Modification of amino groups". Toxicon. 29 (7): 819–826. Bibcode:1991Txcn...29..819M. doi:10.1016/0041-0101(91)90218-G. ISSN 0041-0101. PMID 1681602.
- ^ a b c d e f g h Zykova, Tatiana A.; Vinokurov, Leonid M.; Kozlovskaya, Emma P.; Elyakov, Georgy B. (1985). "Amino acid sequence of neurotoxin III from the sea anemone Radianthus macrodactylus". Bioorganicheskaya Khimiya. 11: 302–310.
- ^ Monastyrnaya, Margarita Mikhailovna; Kalina, Rimma Sergeevna; Kozlovskaya, Emma Pavlovna (2023). "The Sea Anemone Neurotoxins Modulating Sodium Channels: An Insight at Structure and Functional Activity after Four Decades of Investigation". Toxins. 15 (1): 8. doi:10.3390/toxins15010008. ISSN 2072-6651. PMC 9863223. PMID 36668828.
- ^ Nabiullin, A. A.; Odinokov, Stanislav E.; Vozhova, E. I.; Kozlovskaya, Emma. P.; Elyakov, Georgy B. (1982). "A circular-dichroism study on the conformational stability of toxin-I from sea anemone Radianthus macrodactylus". Bioorganicheskaya Khimiya. 8 (12): 1644–1648.
- ^ Kem, William R.; Parten, Benne; Pennington, Michael W.; Price, David A.; Dunn, Ben M. (1989-04-18). "Isolation, characterization, and amino acid sequence of a polypeptide neurotoxin occurring in the sea anemone Stichodactyla helianthus". Biochemistry. 28 (8): 3483–3489. doi:10.1021/bi00434a050. ISSN 0006-2960. PMID 2568126.
- ^ Wilcox, G R; Fogh, R H; Norton, R S (1993). "Refined structure in solution of the sea anemone neurotoxin ShI". Journal of Biological Chemistry. 268 (33): 24707–24719. doi:10.1016/s0021-9258(19)74523-2. ISSN 0021-9258. PMID 7901218.
- ^ a b c d e f g h i Kalina, Rimma S.; Peigneur, Steve; Zelepuga, Elena A.; Dmitrenok, Pavel S.; Kvetkina, Aleksandra N.; Kim, Natalia Y.; Leychenko, Elena V.; Tytgat, Jan; Kozlovskaya, Emma P.; Monastyrnaya, Margarita M.; Gladkikh, Irina N. (2020). "New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa". Toxins. 12 (1): 44. doi:10.3390/toxins12010044. ISSN 2072-6651. PMC 7020476. PMID 31936885.
- ^ a b Moran, Yehu; Cohen, Lior; Kahn, Roy; Karbat, Izhar; Gordon, Dalia; Gurevitz, Michael (2006-07-01). "Expression and Mutagenesis of the Sea Anemone Toxin Av2 Reveals Key Amino Acid Residues Important for Activity on Voltage-Gated Sodium Channels". Biochemistry. 45 (29): 8864–8873. doi:10.1021/bi060386b. ISSN 0006-2960. PMID 16846229.
- ^ a b Honma, Tomohiro; Shiomi, Kazuo (2006-01-01). "Peptide Toxins in Sea Anemones: Structural and Functional Aspects". Marine Biotechnology. 8 (1): 1–10. Bibcode:2006MarBt...8....1H. doi:10.1007/s10126-005-5093-2. ISSN 1436-2236. PMC 4271777. PMID 16372161.
- ^ Mahnir, Vladimir M.; Kozlovskaya, Emma P.; Elyakov, Georgy B. (1989-01-01). "Modification of arginine in sea anemone toxin RTX-III from Radianthus macrodactylus". Toxicon. 27 (10): 1075–1084. Bibcode:1989Txcn...27.1075M. doi:10.1016/0041-0101(89)90001-9. ISSN 0041-0101. PMID 2573177.
