Functional Genomics in Reveal Diverse Muscle NAChRs and Differences Between Cholinergic Anthelmintics

Many techniques for studying functional genomics of important target sites of anthelmintics have been restricted to because they have failed when applied to animal parasites. To overcome these limitations, we have focused our research on the human nematode parasite which causes elephantiasis. Here, we combine single-cell PCR, whole muscle cell patch clamp, motility phenotyping (Worminator), and dsRNA for RNAi for functional genomic studies that have revealed, in vivo, four different muscle nAChRs ( and ). The cholinergic anthelmintics had different selectivities for these receptors. We show that motility and patch-clamp responses to levamisole and pyrantel, but not morantel or nicotine, require the and/or genes. Derquantel behaved as a competitive antagonist and distinguished nAChRs activated by morantel ( 13.9 nM), nAChRs activated by pyrantel ( 126 nM), and nAChRs activated by levamisole ( 0.96 µM) and bephenium. Derquantel was a noncompetitive antagonist of nicotine, revealing type nAChRs. The presence of four diverse nAChRs on muscle is perhaps surprising and not predicted from the model. The diverse nAChRs represent distinguishable drug targets with different functions: Knockdown of ( and/or receptors) inhibited motility but knockdown of ( and/or receptors) did not.