A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans

RODRIGUEZ ARAUJO, N.; HERNANDO, G.; CORRADI, J.; BOUZAT, C.

Ciudad Autónoma de Buenos Aires

Congreso; XLIX Reunión Anual SAB; 2021

Sociedad Argentina de Biofísica (SAB)

Ivermectin (IVM) and piperazine (PZE), which are agonists of Glutamate-gated chloridechannels and GABAA receptors, respectively, are marketed drugs used in anthelmintictherapy. Here we discovered a novel target of these drugs by evaluating their effects onthe free-living nematode C. elegans. Nematodes contain a homomeric 5HT-gated chloridechannel, MOD-1, that modulates locomotor behavior. Due to its absence in vertebrates,MOD-1 emerges as an attractive anthelmintic drug target. By electrophysiologicalrecordings from cells expressing MOD-1, we deciphered its pharmacological propertiesand searched for novel ligands. Macroscopic currents activated by 5-HT showed thatMOD-1 desensitizes slowly and recovers from desensitization in about 1 s. Dose-responsecurves revealed an EC50 for 5-HT of ~1 µM, similar to that of 5-HT3A receptors. The partialagonists tryptamine and 2-Me-5HT showed very different efficacies between MOD-1 and5-HT3A receptors. IVM and PZE did not activate MOD-1 but acted as non-competitiveantagonists. IVM produced a slight and irreversible inhibition whereas PZE led to aprofound and reversible inhibition, indicating that MOD-1 may be involved in theiranthelmintic effects. Also, the specific GABAA receptor agonists, muscimol andisoguvacine, inhibited MOD-1 currents. We performed locomotor activity assays of wildtype (WT) and mutant strains to establish MOD-1 as a novel anthelmintic target. We foundthat 5-HT produced a rapid paralysis of WT worms while the MOD-1 mutant strain wasresistant, thus confirming MOD-1 as the functional target of 5-HT. The exposure of wormsto 5-HT combined with IVM or PZE at concentrations at which they do not act at theircanonical receptors reduced the 5-HT paralyzing effect, thus supporting the negativemodulation of MOD-1 detected in electrophysiological recordings. This study contributesto our understanding of the action of drugs to treat parasitic diseases and to guide futuredrug discovery efforts.