Document Detail

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes.
MedLine Citation:
PMID:  22711816     Owner:  NLM     Status:  MEDLINE    
African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of-function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR.
Nicola Baker; Lucy Glover; Jane C Munday; David Aguinaga Andrés; Michael P Barrett; Harry P de Koning; David Horn
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-18
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-04     Completed Date:  2012-09-18     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10996-1001     Citation Subset:  IM    
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MeSH Terms
Aquaporin 2 / genetics,  metabolism*
Aquaporin 3 / genetics,  metabolism
Cell Line
Drug Resistance / physiology
Flagella / metabolism
High-Throughput Screening Assays
Melarsoprol / pharmacology*
Molecular Sequence Data
Pentamidine / pharmacology
Trypanocidal Agents / pharmacology
Trypanosoma brucei brucei / drug effects*,  growth & development,  metabolism*
Trypanosomiasis / drug therapy*,  metabolism,  parasitology*
Tsetse Flies / parasitology
Grant Support
085349//Wellcome Trust; 093010/Z/10/Z//Wellcome Trust; 84733//Medical Research Council; G0701258//Medical Research Council
Reg. No./Substance:
0/Aquaporin 2; 0/Trypanocidal Agents; 158801-98-0/Aquaporin 3; 673LC5J4LQ/Pentamidine; ZF3786Q2E8/Melarsoprol

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