In the summer of 1935, a young man was enjoying a stroll along the shores of Haymen Island off the coast of Australia when he tripped over an attractive – but live – cone shell which would have made an excellent paperweight back home. Such a destiny, however, was not to the shell’s taste and it retorted by stinging the man’s hand. Numbness, stiffness and soon paralysis of the victim’s limbs occurred before he became unconscious and dropped into a deep coma followed by death within the space of five hours. As for the cone shell, despite its rather strong protest, it didn’t gain its hoped-for freedom and was shipped back to the mainland.
The shell turned out to be a venomous cone shell known as Conus geographus. There are more than 500 different species of predatory cone snails that all have about 100 different active components in their venom. One of these active components is contulakin-G: a neurotensin. Neurotensins – of which there are many kinds – are neurotransmitters which bind to specific cell receptors and are found both in the central nervous system and the peripheral one, where they are involved in activities as diverse as thermoregulation, blood pressure, the perception of pain or digestion.
Contulakin-G (from the Filipino ‘tulakin’ meaning ‘prod’) is not only the first invertebrate neurotensin to have been discovered but also the first whose structure has been fully determined. It is barely 16 amino acids long but sports a posttranslational novelty in Conus peptides: an O-glycosylated threonine residue. When injected into the brain of mice, it makes them sluggish… Indeed, when the mice are prodded, instead of beating a hasty retreat, they heave themselves onto their legs and take a step or two before subsiding again.
Biologists think that contulakin-G probably competes with mice neurotensins by binding to their receptors, thereby creating all kinds of dysfunction – in this case sluggishness which would be ideal for catching prey or warding off predators. The glycan moiety could have something to do with stabilizing the peptide’s structure or conferring receptor-binding specificity for instance. What is more, besides being toxic to other creatures, contulakin-G could very well have an endogenous neurotensin function.
Neurotensins are probably involved in illnesses as serious as Parkinson’s disease, schrizophrenia, cardiovascular troubles or various cancers, so getting to know them well is of biomedical importance. It is likely that the cone shell the young stroller picked up did not intend to eat him but was acting in self-defense – a high price to pay for a paperweight.