(a) Specimen of Calliophis bivirgatus, the blue coral
snake (Photo by Tom Charlton). (b) Dissected preserved
112 cm Calliophis bivirgatus specimen with 29 cm elongated
venom glands (arrows).
With its combination of electric blue dorsolateral stripes and neon red head, tail, and ventral scales, the blue coral snake, Calliophis bivirgatus, is arguably one of the world’s most striking species of snake. An encounter with one is high on the list for many reptile enthusiasts and nature photographers visiting southern Thailand, Malaysia, Singapore, and western Indonesia. The species is of additional interest to anatomists and toxinologists studying the evolution and diversification of the snake venom system as it (along with its congener C. intestinalis) possesses novel elongated venom glands that extend up to one quarter of the length of its body. It is also of medical significance as, in spite of only a small handful of confirmed bites, it has been responsible for at least one human fatality, is suspected of causing at least one more, and has no known antivenom. In spite of these high levels of interest, the venom has been subject to relatively few studies. Studies that examined the toxin content of the venom concluded that all the three-finger toxins present were exclusively cytotoxic in their effects. However, this limited scope of activity attributed to the venom was reflective of the very narrow scope of assays performed and cytotoxicity was largely assumed based on similarity of partial sequences to other toxin types from other snakes rather than full activity characterisation. One study, which examined the usefulness of Taiwan antivenom, preincubated the venom with antivenom (a clinically unrealistic situation) and even then required very high doses to exert any meaningful level of inhibition.
In a new paper Yang et al. (2016) show that the venom is unique in producing spastic paralysis, in contrast to the flaccid paralysis typically produced by neurotoxic snake venoms. The toxin responsible, is named calliotoxin (δ-elapitoxin-Cb1a), a three-finger toxin (3FTx). The calliotoxin molecule has a form of neurotoxicity, previously known from cone snail and scorpion venoms, and is identified for the first time from the venom of a snake. Calliotoxin shifts the voltage-dependence of NaV1.4 activation to more hyperpolarised potentials, inhibits inactivation, and produces large ramp currents, consistent with its profound effects on contractile force in an isolated skeletal muscle preparation. Voltage-gated sodium channels (NaV) are a particularly attractive pharmacological target as they are involved in almost all physiological processes including action potential generation and conduction. Accordingly, venom peptides that interfere with NaV function provide a key defensive and predatory advantage to a range of invertebrate venomous species including cone snails, scorpions, spiders, and anemones. Enhanced activation or delayed inactivation of sodium channels by toxins is associated with the extremely rapid onset of tetanic/excitatory paralysis in envenomed prey animals. A strong selection pressure exists for the evolution of such toxins where there is a high chance of prey escape. However, despite their prevalence in other venomous species, toxins causing delay of sodium channel inhibition have never previously been described in vertebrate venoms. Here we show that NaV modulators, convergent with those of invertebrates, have evolved in the venom of the long-glanded coral snake. Calliotoxin represents a functionally novel class of 3FTx and a structurally novel class of NaV toxins that will provide significant insights into the pharmacology and physiology of NaV. The toxin represents a remarkable case of functional convergence between invertebrate and vertebrate venom systems in response to similar selection pressures. These results underscore the dynamic evolution of the Toxicofera reptile system and reinforces the value of using evolution as a roadmap for biodiscovery.
Yang DC, Deuis JR, Dashevsky D, Dobson J, Jackson TN, Brust A, Xie B, Koludarov I, Debono J, Hendrikx I, Hodgson WC. 2016. The Snake with the Scorpion’s Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus). Toxins. 8(10):303.