Diethylcarbamazine elicits Ca signals through TRP-2 channels that are potentiated by emodepside in muscles.

Filarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused by and spp. affecting over 120 million people. Heavy infections can lead to elephantiasis, which has serious effects on individuals' lives. Although current anthelmintics are effective at killing microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open transient receptor potential (TRP) channels in the muscles of adult female leading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside on inhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trial for the treatment of river blindness. Here, we have studied the effects of diethylcarbamazine on single muscle cells by measuring the change in Ca fluorescence in the muscle using Ca-imaging techniques. Diethylcarbamazine interacts with the transient receptor potential channel, C classification (TRPC) ortholog receptor TRP-2 to promote Ca entry into the muscle cells, which can activate Slopoke (SLO-1) Ca-activated K channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca entry that is increased by emodepside activation of SLO-1 K channels.