• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • In conclusion this study provides


    In conclusion, this study provides the first investigation of role of ACC receptors in parasitic nematodes. While research using C. elegans to evaluate anthelmintic targets is an excellent tool to provide relevant information, research on similar targets in parasitic nematode can provide key information on whether a rational drug design approach might be worthwhile. While there is still much more to be learned about the role of ACC receptors in parasitic nematodes it is clear that comparing the function of the LGCC family in free-living and parasitic nematodes can potentially lead to the discovery of future anthelmintic targets and a better understanding of the evolution of parasitism.
    Declarations of interest
    Acknowledgements Research was funded by the Natural Science and Engineering Council of Canada (NSERC) (Grant #210290) SGF. The funding body played no role in the design or execution of the study. The authors declare no conflict of interest. We thank Paula Ribeiro, McGill University, for the antibodies used in this study and the many years of mentorship and contribution to the field of helminth neurochemistry.
    Introduction The Cys-loop (cysteine-loop) superfamily of ligand-gated ion channels (LGICs) are a major class of receptor-coupled ion channels. These channels have been widely studied in invertebrate organisms for decades because they play key roles in the nervous system, making them prime targets for insecticides and nematocides (Del Castillo et al., 1963). The channel contains five protein subunits, encoded by the same or different subunit genes, all situated around a central aqueous pore. Each subunit contains an extracellular N-terminal ligand binding domain, where two cysteine residues, situated 13 amino RSL3 residues apart, form a disulfide bond, as well as four transmembrane domains (TM1-TM4), and an extracellular C-terminus. These subunits can assemble as homo-oligomers, containing one subunit type, or hetero-oligomers, containing multiple subunit types (Sine and Engel, 2006). Upon ligand binding, these channels elicit fast inhibitory or excitatory neurotransmission. In mammals, excitatory channels include nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine (5-HT3) serotonin receptors, and inhibitory channels include gamma-aminobutyric acid (GABA) and glycine receptors (Ortells and Lunt, 1995). Invertebrates, specifically parasitic and free-living nematodes, contain a variety of LGIC subunit types which are not found in vertebrates (Jones and Sattelle, 2008). These channels have been shown to be gated by neurotransmitters including GABA (Bamber et al., 1999; Siddiqui et al., 2010), glutamate (Cully et al., 1994), tyramine (Pirri et al., 2009), acetylcholine (ACh) (Putrenko et al., 2005), and serotonin (Ranganathan et al., 2000). The ligand-binding site of cys-loop receptors is located at the interface of two adjacent subunits, which are loops A-C on the principal subunit and loops D-G on the complementary subunit (Hibbs and Gouaux, 2011). Each receptor has a different ligand-binding domain that contain various residues, which allow for the selection of different molecular agonists. There are key aromatic residues in the binding site of LGICs that have shown to be involved in ligand binding (Beene et al., 2004). Many neurotransmitters contain a cationic center that acts to stabilize the interaction between a cation and the negative electrostatic potential on the face of the aromatic ring. This is known as cation-π interactions (Beene et al., 2002). These cation- π interactions involve aromatic amino acids (either phenylalanine, tyrosine, or tryptophan) in the ligand binding region (Dougherty, 1996). While the importance of aromatic residues for the function of the agonist binding pocket is widely shared across the phyla, there is variability across different receptors with respect the type of aromatic residues that contribute to binding and their location within the binding loops (Lynagh and Pless, 2014). This highlights the promiscuous nature of neurotransmitter binding across a variety of receptors in animals.