Sea anemone toxins affecting voltage-gated sodium channels – molecular and evolutionary features

Abstract

The venom of sea anemones is rich in low molecular weight proteinaceous neurotoxins that vary greatly in structure, site of action, and phyletic (insect, crustacean or vertebrate) preference. This toxic versatility likely contributes to the ability of these sessile animals to inhabit marine environments co-habited by a variety of mobile predators. Among these toxins, those that show prominent activity at voltage-gated sodium channels and are critical in predation and defense, have been extensively studied for more than three decades. These studies initially focused on the discovery of new toxins, determination of their covalent and folded structures, understanding of their mechanisms of action on different sodium channels, and identification of the primary sites of interaction of the toxins with their channel receptors. The channel binding site for Type I and the structurally unrelated Type III sea anemone toxins was identified as neurotoxin receptor site 3, a site previously shown to be targeted by scorpion alpha-toxins. The bioactive surfaces of toxin representatives from these two sea anemone types have been characterized by mutagenesis. These analyses pointed to heterogeneity of receptor site 3 at various sodium channels. A turning point in evolutionary studies of sea anemone toxins was the recent release of the genome sequence of Nematostella vectensis, which enabled analysis of the genomic organization of the corresponding genes. This analysis demonstrated that Type I toxins in Nematostella and other species are encoded by gene families and suggested that these genes developed by concerted evolution. The current review provides a brief historical description of the discovery and characterization of sea anemone toxins that affect voltage-gated sodium channels and delineates recent advances in the study of their structure-activity relationship and evolution.

Neurotoxin localization to ectodermal gland cells uncovers an alternative mechanism of venom delivery in sea anemones

“…Among the better studied cnidarian venom components are the potent sea anemone Type I neurotoxins. These are peptides of 46-51 amino acids that inhibit the inactivation of voltagegated sodium channels, thus inducing paralysis of prey or predator (reviewed in [13,14]). …”

Biological Activity of Insecticidal Toxins: Structural Basis, Site-Directed Mutagenesis and Perspectives

“…Venom analysis shows a significant collection of low molecular weight toxins: ~20 kDa pore-forming toxins, 3.5-6.5 kDa voltage-gated potassium channel-active toxins and 3-5 kDa polypeptide toxins active on voltage-gated sodium channels (Navs) (Moran et al, 2009). [A Nav has a central role in the excitability of animals.…”

“…Av2 has shown a clear preference for insect Nav from the assessment of toxin effects on the Drosophila melanogaster sodium channel (DmNav1) expressed in Xenopus laevis oocytes (Moran et al, 2009;Warmke et al, 1997). Hence, mutagenesis offers a means of examining residues thought to be important for Av2 activity on insect Navs.…”

What Hydra can teach us about chemical ecology how a simple, soft organism survives in a hostile aqueous environment

“…Given the long history of Hydra as a research model, dating back to studies by Abraham Trembley (Trembley, 1744), it is surprising how little is known about the chemical arsenal of Hydra, especially in comparison to other cnidarians such as sea anemones (Moran et al, 2009a) (see also the special issue on cnidarian toxins and venoms in Toxicon 54, 2009). Initial studies of Hydra venom focused on describing the physiological effect of the venom on model organisms such as Drosophila, which simulate arthropod prey, and on isolated heart muscle.…”

“…The chemical ecology of Hydra 607 mainly by short (4-7kDa) peptide neurotoxins (Fry et al, 2009, Moran et al, 2009a, Morgenstern et al, 2011, Olivera, 2002, Terlau et al, 1996. Typically tens or even hundreds of such peptide neurotoxins are found in every venom cocktail, with different neurotoxins evolving to interfere with nerve and muscle activity at many different locations (e.g.…”