Discovery of the Nicotinic Receptor Toxin Anabaseine in a Polystiliferan Nemertean

Abstract

Nemerteans (also called Nemertines) are a phylum of predominantly marine worms that use toxins to capture prey and to defend themselves against predators. Hoplonemerteans have a proboscis armed with one or more stylets used in prey capture and are taxonomically divided into Order Monostilifera, whose members possess a single large proboscis stylet, and Order Polystilifera, whose members have multiple small stylets. Many monostiliferans contain alkaloidal toxins, including anabaseine, that stimulate and then desensitize nicotinic acetylcholine receptors that are present in all animals. These compounds also interact with pyridyl chemoreceptors in crustaceans, reducing predation and larval settlement. Anabaseine has been a lead compound in the design of alpha7 nicotinic acetylcholine receptor agonists like GTS-21 (also called DMXBA) to treat disorders of cognition such as Alzheimer’s disease and schizophrenia. These drug candidates also display anti-inflammatory activities of potential medical importance. Most polystiliferans live deep in open oceans and are relatively inaccessible. We fortunately obtained two live specimens of a large benthic polystiliferan, Paradrepanophorus crassus (Pc), from the coast of Spain. MS and NMR analyses of the Ehrlich’s reagent derivative allowed identification of anabaseine. A spectrophotometric assay for anabaseine, also based on its reaction with Ehrlich’s reagent, revealed high concentrations of anabaseine in the body and proboscis. Apparently, the biosynthetic mechanism for producing anabaseine was acquired early in the evolution of the Hoplonemertea, before the monostiliferan-polystiliferan divergence.

Venomous Noodles: The Evolution of Toxins in Nemertea through Positive Selection and Gene Duplication

“…Both proteinaceous [9,12,21] and non-proteinaceous [8,[22][23][24][25] toxic compounds have been isolated from the mucus of different nemertean species. There is evidence that some of these toxins have potential application as pesticide [13].…”

“…Later, more pyridine alkaloids were characterized from other hoplonemernteans and characterized as neurotoxic to invertebrates [8,23] and, in a smaller degree, mammals [22]. Recently, it was proposed that these toxins evolved before the the monostiliferan-polystiliferan divergence [24]. TTX, a strong paralytic compound that blocks sodium channels [26], was detected in all three Nemertea orders [25], but was found to be specially abundant in the Palaeonemertea Cephalothrix simula [25].…”