A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.

<h4>Background</h4>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)...

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Autores principales:	Taisaku Nogi, Dan Zhang, John D Chan, Jonathan S Marchant
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/54ba41af79114d84ae2c8babca92ef9a
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spelling	oai:doaj.org-article:54ba41af79114d84ae2c8babca92ef9a2021-11-25T06:33:18ZA novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.1935-27271935-273510.1371/journal.pntd.0000464https://doaj.org/article/54ba41af79114d84ae2c8babca92ef9a2009-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19554083/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735<h4>Background</h4>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.<h4>Methods and findings</h4>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) beta subunits, but not by knockdown of a VOCC alpha subunit. At higher doses of PZQ, knockdown of VOCC beta subunits also conferred resistance to PZQ in lethality assays.<h4>Conclusions</h4>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 beta subunits provides the first genetic evidence implicating a molecular target crucial for in vivo PZQ activity and supports the 'VOCC hypothesis' of PZQ efficacy. Further, in terms of regenerative biology and Ca(2+) signaling, these data highlight a novel role for voltage-operated Ca(2+) entry in regulating in vivo stem cell differentiation and regenerative patterning.Taisaku NogiDan ZhangJohn D ChanJonathan S MarchantPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 3, Iss 6, p e464 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Taisaku Nogi Dan Zhang John D Chan Jonathan S Marchant A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
description	<h4>Background</h4>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.<h4>Methods and findings</h4>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) beta subunits, but not by knockdown of a VOCC alpha subunit. At higher doses of PZQ, knockdown of VOCC beta subunits also conferred resistance to PZQ in lethality assays.<h4>Conclusions</h4>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 beta subunits provides the first genetic evidence implicating a molecular target crucial for in vivo PZQ activity and supports the 'VOCC hypothesis' of PZQ efficacy. Further, in terms of regenerative biology and Ca(2+) signaling, these data highlight a novel role for voltage-operated Ca(2+) entry in regulating in vivo stem cell differentiation and regenerative patterning.
format	article
author	Taisaku Nogi Dan Zhang John D Chan Jonathan S Marchant
author_facet	Taisaku Nogi Dan Zhang John D Chan Jonathan S Marchant
author_sort	Taisaku Nogi
title	A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
title_short	A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
title_full	A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
title_fullStr	A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
title_full_unstemmed	A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
title_sort	novel biological activity of praziquantel requiring voltage-operated ca2+ channel beta subunits: subversion of flatworm regenerative polarity.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/54ba41af79114d84ae2c8babca92ef9a
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A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity.

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