Plasmodium falciparum Regulatory Subunit of cAMP-Dependent PKA and Anion Channel Conductance

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Abstract
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. By replicating within red blood cells malaria parasites are largely hidden from immune recognition, but within mature erythrocytes nutrients are limiting and accumulation of potentially hazardous metabolic end products can rapidly become critical. In order to survive within red blood cells malaria parasites, therefore, alter the permeability of the erythrocyte plasma membrane either by up-regulating existing carriers, or by creating new permeation pathways. Recent electrophysiological studies of Plasmodium-infected erythrocytes have demonstrated that these changes reflect trans-membrane transport through ion channels in the infected erythrocyte plasma membrane. Protein phosphorylation has been documented in protozoan parasites for a number of years and is implicated in key processes of both parasites and parasitized host cells. It has been established that cAMP-dependent regulated pathways are able to activate ion channels in the red cell membrane and a better understanding of how the parasite manipulates cAMP-dependent signaling to activate anion channels could be important in developing novel strategies for future anti-malarial chemotherapies.