Plasmodium falciparum regulatory subunit of cAMP-dependent PKA and anion channel conductance.
Malaria symptoms occur during Plasmodium falciparum development into red blood cells. During this process, the parasites make substantial modifications to the host cell in order to facilitate nutrient uptake and aid in parasite metabolism. One significant alteration that is required for parasite development is the establishment of an anion channel, as part of the establishment of New Permeation Pathways (NPPs) in the red blood cell plasma membrane, and we have shown previously that one channel can be activated in uninfected cells by exogenous protein kinase A. Here, we present evidence that in P. falciparum-infected red blood cells, a cAMP pathway modulates anion conductance of the erythrocyte membrane. In patch-clamp experiments on infected erythrocytes, addition of recombinant PfPKA-R to the pipette in vitro, or overexpression of PfPKA-R in transgenic parasites lead to down-regulation of anion conductance. Moreover, this overexpressing PfPKA-R strain has a growth defect that can be restored by increasing the levels of intracellular cAMP. Our data demonstrate that the anion channel is indeed regulated by a cAMP-dependent pathway in P. falciparum-infected red blood cells. The discovery of a parasite regulatory pathway responsible for modulating anion channel activity in the membranes of P. falciparum-infected red blood cells represents an important insight into how parasites modify host cell permeation pathways. These findings may also provide an avenue for the development of new intervention strategies targeting this important anion channel and its regulation.
Merckx
Anaïs
A
INSERM U609, Wellcome Center for Molecular Parasitology, Glasgow Biomedical Research Centre, Glasgow, Scotland, United Kingdom.
Nivez
Marie-Paule
MP
Bouyer
Guillaume
G
Alano
Pietro
P
Langsley
Gordon
G
Deitsch
Kirk
K
Thomas
Serge
S
Doerig
Christian
C
Egée
Stéphane
S
D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000187:drug effects / Q000502:physiology*; D000838:Anions; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D017125:Genes, Protozoan; D006790:Host-Parasite Interactions; D015640:Ion Channel Gating; D007473:Ion Channels; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010963:Plasmodium falciparum / Q000472:pathogenicity / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D050994:Voltage-Dependent Anion Channels / Q000187:drug effects / Q000502:physiology*
D001457:Anion Exchange Protein 1, Erythrocyte; D000838:Anions; D007473:Ion Channels; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D050994:Voltage-Dependent Anion Channels; D017868:Cyclic AMP-Dependent Protein Kinases