Eat-2-ing away: acetylcholine receptor binding subunits lacking vicinal cysteines, a new pharmacophore for mitigation of plant parasitic infection.

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Chemicals acting on neuromuscular transmission that control insects and nematode movement have provided successful pest management. An important criterion in ongoing development of this approach is selective toxicityThis allows treatments to act as potent pest control while having limited deleterious effect on non-harmful organisms. Conventionally, this is addressed by defining receptor classes selectively found between phyla and species. We have recently established a tissue selective sensitivity in the cholinergic transmission that pharmacologically discriminates between locomotion and feeding in nematodes (Gonzalez, J Biol Chem in submission). This difference is due to the distinct nature of the major acetylcholine receptors underpinning cholinergic transmission at these neuromuscular junctions. Pharyngeal transmission is dependent on an under investigated excitatory nicotinic acetylcholine receptor called EAT-2. This receptor is among an emerging class of homo-oligomeric receptors activated by the endogenous agonist acetylcholine. However, EAT-2 is unique amongst nicotinic receptors in lacking the signature vicinal cysteine in the highly evolutionary conserved loop C of the agonist binding site. It was previously assumed that this vicinal cysteine was essential for acetylcholine receptor activation in both homo and hetero-oligomeric receptors. This feature of the agonist binding site exists in the even more poorly investigated acetylcholine gated chloride channels (PLoS Pathog 2020 16(4):e1008396). This highlights that nicotinic receptors can present a distinct pharmacophore to provide a route to selective anthelmintic chemicals. Importantly, the prototype EAT-2 controls feeding in the model organism C. elegans and is found in other nematodes including the plant parasitic nematodes. The proposal will seek to identify selective pharmacology of EAT-2 and other non-vicinal acetylcholine receptors. The student will probe their functional role in key plant parasitic nematodes and address if this under investigated determinant of the neuromuscular function can act as credible target for the chemical mitigation of nematode pests.