Human and rodent erythrocytes are known to be highly permeable to glycerol. Aquaglyceroporin aquaporin (AQP)3 is the major glycerol channel in human and rat erythrocytes. However, AQP3 expression has not been observed in mouse erythrocytes. Here we report the presence of an aquaglyceroporin, AQP9, in mouse erythrocytes. AQP9 levels rise as reticulocytes mature into erythrocytes and as neonatal pups develop into adult mice. Mice bearing targeted disruption of both alleles encoding AQP9 have erythrocytes that appear morphologically normal. Compared with WT cells, erythrocytes from AQP9-null mice are defective in rapid glycerol transport across the cell membrane when measured by osmotic lysis, [ 14 C]glycerol uptake, or stopped-flow light scattering. In contrast, the water and urea permeabilities are intact. Although the physiological role of glycerol in the normal function of erythrocytes is not clear, plasma glycerol is an important substrate for lipid biosynthesis of intraerythrocytic malarial parasites. AQP9-null mice at the age of 4 months infected with Plasmodium berghei survive longer during the initial phase of infection compared with WT mice. We conclude that AQP9 is the major glycerol channel in mouse erythrocytes and suggest that this transport pathway may contribute to the virulence of intraerythrocytic stages of malarial infection.Plasmodium berghei ͉ aquaglyceroporin A quaglyceroporins are transmembrane proteins belonging to the aquaporin (AQP) water channel family (1). Aquaglyceroporins are the only known glycerol channels in mammalian cells. Among 13 identified mammalian aquaporins, AQP3, AQP7, AQP9, and AQP10 represent the aquaglyceroporin subfamily on the basis of their amino acid sequences and solute permeabilities (1). Aquaglyceroporins are also permeable to urea and water when expressed in Xenopus laevis oocytes (1).The first defined water channel, AQP1, was discovered in human erythrocytes (2). The high expression and water permeability of AQP1 in erythrocytes led to the hypothesis that AQP1 is important in adaptation to dramatic osmolarity changes in the circulation (2). In addition to high water permeability, human and rodent erythrocytes are known to be highly permeable to urea and glycerol (3). AQP3 has been identified as the main channel for glycerol transport in human and rat erythrocytes (4). AQP3 has not been detected in mouse erythrocytes, and the glycerol permeability of mouse erythrocytes from AQP3 knockout mice has been shown to not be affected by gene deletion (5). We revisited this question and detected AQP9 expression in mouse erythrocytes. By using AQP9-null mice, we provide evidence that AQP9 is the major pathway for glycerol transport in mouse erythrocytes.The physiological role of aquaglyceroporins in erythrocytes is still not clear. However, recent studies indicate that aquaglyceroporins AQP7 and AQP9 participate in metabolism. Under fasting conditions, up-regulated AQP7 expression in adipocytes facilitates the release of glycerol, which can then be transported through the ...

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The malaria parasite can use host plasma glycerol for lipid biosynthesis and membrane biogenesis during the asexual intraerythrocytic development. The molecular basis for glycerol uptake into the parasite is undefined. We hypothesize that the Plasmodium aquaglyceroporin provides the pathway for glycerol uptake into the malaria parasite. To test this hypothesis, we identified the orthologue of Plasmodium falciparum aquaglyceroporin (PfAQP) in the rodent malaria parasite, Plasmodium berghei (PbAQP), and examined the biological role of PbAQP by performing a targeted deletion of the PbAQP gene. PbAQP and PfAQP are 62% identical in sequence. In contrast to the canonical NPA (Asn-Pro-Ala) motifs in most aquaporins, the PbAQP has NLA (Asn-Leu-Ala) and NPS (Asn-Leu-Ser) in those positions. PbAQP expressed in Xenopus oocytes was permeable to water and glycerol, suggesting that PbAQP is an aquaglyceroporin. In P. berghei, PbAQP was localized to the parasite plasma membrane. The PbAQP-null parasites were viable; however, they were highly deficient in glycerol transport. In addition, they proliferated more slowly compared with the WT parasites, and mice infected with PbAQP-null parasites survived longer. Taken together, these findings suggest that PbAQP provides the pathway for the entry of glycerol into P. berghei and contributes to the growth of the parasite during the asexual intraerythrocytic stages of infection. In conclusion, we demonstrate here that PbAQP plays an important role in the blood-stage development of the rodent malaria parasite during infection in mice and could be added to the list of targets for the design of antimalarial drugs.falciparum ͉ knockout ͉ glycerol