a novel biological activity of praziquantel requiring voltage-operated ca2+ channel β subunits subversion of flatworm regenerative polarity一种新型生物活性需要压控ca2 +频道β亚基的吡喹酮subversion的扁形虫再生极性.pdfVIP

A Novel Biological Activity of Praziquantel Requiring Voltage-Operated Ca2+ Channel b Subunits: Subversion of Flatworm Regenerative Polarity Taisaku Nogi, Dan Zhang, John D. Chan, Jonathan S. Marchant* Department of Pharmacology and The Stem Cell Institute, University of Minnesota Medical School, Minnesota, United States of America Abstract Background: Approximately 200 million people worldwide harbour parasitic flatworm infections that cause schistosomiasis. A single drug—praziquantel (PZQ)—has served as the mainstay pharmacotherapy for schistosome infections since the 1980s. However, the relevant in vivo target(s) of praziquantel remain undefined. Methods and Findings: Here, we provide fresh perspective on the molecular basis of praziquantel efficacy in vivo consequent to the discovery of a remarkable action of PZQ on regeneration in a species of free-living flatworm (Dugesia japonica ). Specifically, PZQ caused a robust (100% penetrance) and complete duplication of the entire anterior-posterior axis during flatworm regeneration to yield two-headed organisms with duplicated, integrated central nervous and organ systems. Exploiting this phenotype as a readout for proteins impacting praziquantel efficacy, we demonstrate that PZQ- evoked bipolarity was selectively ablated by in vivo RNAi of voltage-operated calcium channel (VOCC) b subunits, but not by knockdown of a VOCC a subunit. At higher doses of PZQ, knockdown of VOCC b subunits also conferred resistance to PZQ in lethality assays. Conclusions: This study identifies a new biological activity of the antischistosomal drug praziquantel on regenerative polarity in a species of free-living flatworm. Ablation of the bipolar regenerative phenotype evoked by PZQ via in vivo RNAi of VOCC b subunits provides the first genetic evidence implicating