Schistosome calcium channel beta subunits. Unusual modulatory effects and potential role in the action of the antischistosomal drug praziquantel.
Schistosomes are parasitic flatworms that cause schistosomiasis, a major tropical disease. The current drug of choice against schistosomiasis is praziquantel (PZQ), which has minimal side effects and is potent against all schistosome species. The mode of action of PZQ is unknown, though the drug clearly affects Ca(2+) homeostasis in worms, and there is indirect evidence for interaction of PZQ with schistosome voltage-gated Ca(2+) channels. We have cloned and expressed two Ca(2+) channel beta subunits, one from Schistosoma mansoni and one from Schistosoma japonicum. These two subunits (SmCa(v)beta A and SjCa(v)beta) have structural motifs that differ from those found in other known beta subunits. Surprisingly, coexpression of either SmCa(v)beta A or SjCa(v)beta with a cnidarian (CyCa(v)1) or mammalian (Ca(v)2.3) Ca(2+) channel alpha(1) 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 addition of 100 nm PZQ, which results in a significant increase in current amplitude. Thus, these unusual schistosome beta subunits can confer PZQ sensitivity to an otherwise PZQ-insensitive mammalian Ca(2+) channel, indicating that a possible target for PZQ action is the interaction between beta subunits and pore-forming alpha(1) subunits in schistosomes.
Kohn
A B
AB
Whitney Laboratory, University of Florida, St. Augustine, Florida 32080, USA.
Anderson
P A
PA
Roberts-Misterly
J M
JM
Greenberg
R M
RM
D000595:Amino Acid Sequence; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000032:analysis; D004594:Electrophysiology; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D011223:Praziquantel / Q000494:pharmacology; D012547:Schistosoma / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014982:Xenopus laevis
D000871:Anthelmintics; D015220:Calcium Channels; D018076:DNA, Complementary; D015801:Helminth Proteins; D011223:Praziquantel