title: Erythrocyte peripheral type benzodiazepine receptor/voltage-dependent anion channels are upregulated by Plasmodium falciparum.
abstract: Plasmodium falciparum relies on anion channels activated in the erythrocyte membrane to ensure the transport of nutrients and waste products necessary for its replication and survival after invasion. The molecular identity of these anion channels, termed "new permeability pathways" is unknown, but their currents correspond to up-regulation of endogenous channels displaying complex gating and kinetics similar to those of ligand-gated channels. This report demonstrates that a peripheral-type benzodiazepine receptor, including the voltage dependent anion channel, is present in the human erythrocyte membrane. This receptor mediates the maxi-anion currents previously described in the erythrocyte membrane. Ligands that block this peripheral-type benzodiazepine receptor reduce membrane transport and conductance in P falciparum-infected erythrocytes. These ligands also inhibit in vitro intraerythrocytic growth of P falciparum. These data support the hypothesis that dormant peripheral-type benzodiazepine receptors become the "new permeability pathways" in infected erythrocytes after up-regulation by P falciparum. These channels are obvious targets for selective inhibition in anti-malarial therapies, as well as potential routes for drug delivery in pharmacologic applications.
authors.affiliation: Centre National de la Recherche Scientifique, Université Pierre et Marie Curie Paris, Roscoff, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bouyer
authors.forename: Anne
authors.initials: A
authors.lastname: Cueff
authors.forename: Stéphane
authors.initials: S
authors.lastname: Egée
authors.forename: Justyna
authors.initials: J
authors.lastname: Kmiecik
authors.forename: Yelena
authors.initials: Y
authors.lastname: Maksimova
authors.forename: Edyta
authors.initials: E
authors.lastname: Glogowska
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: Serge L Y
authors.initials: SL
authors.lastname: Thomas
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology*; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D011963:Receptors, GABA-A / Q000097:blood* / Q000187:drug effects; D015854:Up-Regulation; D050994:Voltage-Dependent Anion Channels / Q000097:blood* / Q000235:genetics
chemical_list: D000962:Antimalarials; D001570:Benzodiazepinones; D007546:Isoquinolines; D008024:Ligands; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D050994:Voltage-Dependent Anion Channels; C028513:4'-chlorodiazepam; D003975:Diazepam; C037850:PK 11195