Schistosome calcium channel beta subunits - Unusual modulatory effects andpotential role in the action of the antischistosomal drug praziquantel

Schistosomes are parasitic flatworms that cause schistosomiasis, a major tr opical disease. The current drug of choice against schistosomiasis is prazi quantel (PZQ), which has minimal side effects and is potent against all sch istosome species. The mode of action of PZQ is unknown, though the drug cle arly affects Ca2+ homeostasis in worms, and there is indirect evidence for interaction of PZQ with schistosome voltage-gated Ca2+ channels. We have cl oned and expressed two Ca2+ channel beta subunits, one from Schistosoma man soni and one from Schistosoma japonicum. These two subunits (SmCa(v)betaA a nd SjCa(v)beta) have structural motifs that differ from those found in othe r known beta subunits. Surprisingly, coexpression of either SmCa(v)betaA or SjCa(v)beta with a cnidarian (CyCa(v)1) or mammalian (Ca(v)2.3) Ca2+ chann el a, subunit results in a striking reduction in current amplitude. In the case of Ca(v)2.3, this current reduction can be partially reversed by addit ion of 100 nm PZQ, which results in a significant increase in current ampli tude. Thus, these unusual schistosome beta subunits can confer PZQ sensitiv ity to an otherwise PZQ-insensitive mammalian Ca2+ channel, indicating that a possible target for PZQ action is the interaction between beta subunits and pore-forming alpha (1) subunits in schistosomes.