| Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes. | |
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MedLine Citation:
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PMID: 22711816 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-06-18 |
Journal Detail:
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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:
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Created Date: 2012-07-04 Completed Date: 2012-09-18 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 10996-1001 Citation Subset: IM |
Affiliation:
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Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom. |
| Data Bank Information | |
Bank Name/Acc. No.:
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GENBANK/JX026928 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aquaporin 2 / genetics, metabolism* Aquaporin 3 / genetics, metabolism Cell Line Drug Resistance / physiology Flagella / metabolism High-Throughput Screening Assays Humans 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 | |
ID/Acronym/Agency:
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093010/Z/10/Z//Wellcome Trust; 84733//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Aquaporin 2; 0/Trypanocidal Agents; 100-33-4/Pentamidine; 158801-98-0/Aquaporin 3; 494-79-1/Melarsoprol |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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