Genetic Linkage of Pfmdr1 with Food Vacuolar Solute Import in Plasmodium Falciparum

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2006 Jun 24

PMID 16794577

Citations 69

Authors

Petra Rohrbach

Cecilia P Sanchez

Karen Hayton

Oliver Friedrich

Jigar Patel

Amar Bir Singh Sidhu

Michael T Ferdig

David A Fidock

Michael Lanzer

Affiliations

Soon will be listed here.

Abstract

The P-glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh-1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh-1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh-1 function based on the subcellular distribution of Fluo-4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo-4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite. Genetic, positional cloning and pharmacological data causatively link the food vacuolar Fluo-4 phenotype to those Pgh-1 variants that are associated with altered drug responses. On the basis of our data, we propose that Pgh-1 imports solutes, including certain antimalarial drugs, into the parasite's food vacuole. The implications of our findings for drug resistance mechanisms and testing are discussed.

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