Faculty Collaboration Database

The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel. J Biol Chem 2019 Dec 06;294(49):18873-18880

Date

10/28/2019

Pubmed ID

31653697

Pubmed Central ID

PMC6901322

DOI

10.1074/jbc.AC119.011093

Scopus ID

2-s2.0-85075816525 (requires institutional sign-in at Scopus site)   67 Citations

Abstract

The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. PZQ causes Ca²⁺ influx and spastic paralysis of adult worms and rapid vacuolization of the worm surface. However, the mechanism of action of PZQ remains unknown even after 40 years of clinical use. Here, we demonstrate that PZQ activates a schistosome transient receptor potential (TRP) channel, christened SmTRPM_PZQ, present in parasitic schistosomes and other PZQ-sensitive parasites. Several properties of SmTRPM_PZQ were consistent with known effects of PZQ on schistosomes, including (i) nanomolar sensitivity to PZQ; (ii) stereoselectivity toward (R)-PZQ; (iii) mediation of sustained Ca²⁺ signals in response to PZQ; and (iv) a pharmacological profile that mirrors the well-known effects of PZQ on muscle contraction and tegumental disruption. We anticipate that these findings will spur development of novel therapeutic interventions to manage schistosome infections and broader interest in PZQ, which is finally unmasked as a potent flatworm TRP channel activator.

Author List

Park SK, Gunaratne GS, Chulkov EG, Moehring F, McCusker P, Dosa PI, Chan JD, Stucky CL, Marchant JS

Authors

Evgenii Chulkov Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Sang Kyu Park PhD Research Scientist I in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Anthelmintics
Electrophysiology
Female
HEK293 Cells
Humans
Mice
Praziquantel
Schistosoma
Transient Receptor Potential Channels