8.B.17 The Sea Anemone Peptide Toxin Class III (ShI) Family Cnidaria (sea anemone, coral, jellyfish, and hydroid) toxins target voltage-gated sodium and potassium channels. The sodium channel toxin is a member of the Toxin-4 Superfamily. It binds specifically to the sodium channel (Nav), thereby delaying its inactivation during signal transduction. Thus it strongly stimulates mammalian cardiac muscle contraction.These toxins are reviewed by Moran et al., 2009. Cnidarian toxin families, including peptide neurotoxins (voltage-gated Na⁺ and K⁺ channel-targeting toxins: NaTxs and KTxs, respectively), pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins), and the newly discovered small cysteine-rich peptides (SCRiPs).
This family belongs to the Huwentoxin Superfamily.
References:
Columbus-Shenkar, Y.Y., M.Y. Sachkova, J. Macrander, A. Fridrich, V. Modepalli, A.M. Reitzel, K. Sunagar, and Y. Moran. (2018). Dynamics of venom composition across a complex life cycle. Elife 7:.
Fogh, R.H., W.R. Kem, and R.S. Norton. (1990). Solution structure of neurotoxin I from the sea anemone Stichodactyla helianthus. A nuclear magnetic resonance, distance geometry, and restrained molecular dynamics study. J. Biol. Chem. 265: 13016-13028.
Frazão, B., V. Vasconcelos, and A. Antunes. (2012). Sea anemone (Cnidaria, Anthozoa, Actiniaria) toxins: an overview. Mar Drugs 10: 1812-1851.
Monastyrnaya, M.M., R.S. Kalina, and E.P. Kozlovskaya. (2022). The Sea Anemone Neurotoxins Modulating Sodium Channels: An Insight at Structure and Functional Activity after Four Decades of Investigation. Toxins (Basel) 15:.
Moran, Y., D. Gordon, and M. Gurevitz. (2009). Sea anemone toxins affecting voltage-gated sodium channels--molecular and evolutionary features. Toxicon 54: 1089-1101.
Moran, Y., G. Genikhovich, D. Gordon, S. Wienkoop, C. Zenkert, S. Ozbek, U. Technau, and M. Gurevitz. (2012). Neurotoxin localization to ectodermal gland cells uncovers an alternative mechanism of venom delivery in sea anemones. Proc Biol Sci 279: 1351-1358.
Moran, Y., H. Weinberger, A.M. Reitzel, J.C. Sullivan, R. Kahn, D. Gordon, J.R. Finnerty, and M. Gurevitz. (2008). Intron retention as a posttranscriptional regulatory mechanism of neurotoxin expression at early life stages of the starlet anemone Nematostella vectensis. J. Mol. Biol. 380: 437-443.
Sachkova, M.Y., S.A. Singer, J. Macrander, A.M. Reitzel, S. Peigneur, J. Tytgat, and Y. Moran. (2019). The Birth and Death of Toxins with Distinct Functions: A Case Study in the Sea Anemone Nematostella. Mol Biol Evol 36: 2001-2012.
Examples:
TC#	Name	Organismal Type	Example
8.B.17.1.1	*The Sea Anemone peptide type III neurotoxin, ShI (Fogh et al., 1990), 3-d structure known (1SHI-A).*	Sea Anemone	*Sh1 of Stoichactis helianthus* (P19651)**

8.B.17.1.2	*Sea Anemone peptide neurotoxin Am-3; blocks Na channels. These neurotoxins modulate sodium channels, and structure and functional Aspects have been reviewed (Monastyrnaya et al.* 2022).**	Sea Anemone	*Am-3 of Antheopsis maculata* (P69928)**

8.B.17.1.3	*Anthopleurin-A, AP-A, a heart stimulant; binds voltage-gated Na⁺ channels (structure known) (Frazão et al.* 2012).**	Sea Anemone	AP-A of Anthopleura xanthogrammica (P01530)

8.B.17.1.4	Actitoxin-Avd1f; U-AITX-Avd1f; Av6; Neurotoxin 6 of 72 aas and 2 TMSs.		*U-AITX of Anemonia viridis* (sea anemone)**

8.B.17.1.5	N.vectensis toxin 14 of 85 aas and 1 N-terminal TMS. It binds to site 3 of voltage-gated sodium channels and inhibits the inactivation process (Moran et al. 2008). It is highly active on DmNav1/TipE (Drosophila) and is only weakly active on rat Nav1.4-beta-1/SCN4A-SCN1B, or on human Nav1.5-beta-1/SCN5A-beta-1. This reveals high specificity for arthropod over mammalian channels (Moran et al. 2008). In vivo, when released into the medium, this recombinant toxin induces impaired swimming, paralysis and death of the crustacean A.nauplii within several hours (Moran et al. 2012) and causes paralysis of cherry shrimps immediately after injection at very low doses (Columbus-Shenkar et al. 2018). Its effect on zebrafish (D.rerio) larvae is also rapid, since it induces tail twitching accompanied by impaired swimming after 20 minutes and complete paralysis within 45 minutes (Moran et al. 2012). It has also been observed to cause death of zebrafish larvae within 1 hour (Sachkova et al. 2019).		*Toxin 14 of Nematostella vectensis* (Starlet sea anemone)**

8.B.17.1.6	Delta-actitoxin-Ate Neurotoxin short toxin (III)of 72 aas and 1 N-terminal TMS.		Asctitoxin-Ate of Actinia tenebrosa

8.B.17.1.7	Delta-actitoxin-Avd2c of 61 aas and 1 N-terminal TMS.		Actitoxin-Avd2c of Anemonia viridis

8.B.17.1.8	Delta-stichotoxin-Shd3a of 84 aas with 1 N-termnal TMS.		Delta-stichotoxin-Shd3a ofStichodactyla haddoni (Saddle carpet anemone; Haddon's sea anemone)