Kohn A B, Anderson P A, Roberts-Misterly J M, Greenberg R M
Whitney Laboratory, University of Florida, St. Augustine, Florida 32080, USA.
J Biol Chem. 2001 Oct 5;276(40):36873-6. doi: 10.1074/jbc.C100273200. Epub 2001 Aug 10.
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.
血吸虫是引起血吸虫病（一种主要的热带疾病）的寄生扁虫。目前治疗血吸虫病的首选药物是吡喹酮（PZQ），它副作用极小，对所有血吸虫种类都有效。尽管吡喹酮明显影响虫体中的钙（Ca²⁺）稳态，且有间接证据表明吡喹酮与血吸虫电压门控钙（Ca²⁺）通道相互作用，但其作用方式尚不清楚。我们克隆并表达了两个钙（Ca²⁺）通道β亚基，一个来自曼氏血吸虫，另一个来自日本血吸虫。这两个亚基（SmCa(v)βA和SjCa(v)β）具有与其他已知β亚基不同的结构基序。令人惊讶地是，将SmCa(v)βA或SjCa(v)β与刺胞动物（CyCa(v)1）或哺乳动物（Ca(v)2.3）的钙（Ca²⁺）通道α1亚基共表达会导致电流幅度显著降低。就Ca(v)2.3而言，加入100 nM吡喹酮可部分逆转这种电流降低，这会导致电流幅度显著增加。因此，这些不同寻常的血吸虫β亚基可赋予原本对吡喹酮不敏感的哺乳动物钙（Ca²⁺）通道对吡喹酮的敏感性，表明吡喹酮作用的一个可能靶点是血吸虫中β亚基与形成孔道的α1亚基之间的相互作用。
