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Marc Mosimann Shinobu Goshima Tanja Wenzler Alexandra Lüscher Nobuyuki Uozumi Pascal M?ser 《Eukaryotic cell》2010,9(4):539-546
The molecular mechanisms of K+ homeostasis are only poorly understood for protozoan parasites. Trypanosoma brucei subsp. parasites, the causative agents of human sleeping sickness and nagana, are strictly extracellular and need to actively concentrate K+ from their hosts’ body fluids. The T. brucei genome contains two putative K+ channel genes, yet the trypanosomes are insensitive to K+ antagonists and K+ channel-blocking agents, and they do not spontaneously depolarize in response to high extracellular K+ concentrations. However, the trypanosomes are extremely sensitive to K+ ionophores such as valinomycin. Surprisingly, T. brucei possesses a member of the Trk/HKT superfamily of monovalent cation permeases which so far had only been known from bacteria, archaea, fungi, and plants. The protein was named TbHKT1 and functions as a Na+-independent K+ transporter when expressed in Escherichia coli, Saccharomyces cerevisiae, or Xenopus laevis oocytes. In trypanosomes, TbHKT1 is expressed in both the mammalian bloodstream stage and the Tsetse fly midgut stage; however, RNA interference (RNAi)-mediated silencing of TbHKT1 expression did not produce a growth phenotype in either stage. The presence of HKT genes in trypanosomatids adds a further piece to the enigmatic phylogeny of the Trk/HKT superfamily of K+ transporters. Parsimonial analysis suggests that the transporters were present in the first eukaryotes but subsequently lost in several of the major eukaryotic lineages, in at least four independent events.Potassium (K+) is the most abundant cation in the cytosol of any cell and hence an essential macronutrient for life on earth. Concentrative K+ uptake across the plasma membrane is energized directly by ATPases and indirectly by the negative membrane potential or by coupling, via symport or antiport, to other transport processes such as H+ flux. The ancestry of K+ transporters renders them ideal subjects for phylogenetic comparisons. Indeed, the different kinds of known K+ transporters—pumps, channels, permeases, symporters, and antiporters—are all found in bacteria (43). Eukaryotes do not appear to have invented further mechanisms of K+ transport; on the contrary, some families of K+ transporters were lost over the course of eukaryote evolution, particularly among the metazoa (53).The Trk/HKT superfamily (TC transporter classification 2.A.38 [43]) consists of bacterial TrkH and KtrB, plant HKT, and fungal Trk transporters (15). These proteins share a topology with 8 transmembrane (TM) domains and, sandwiched between odd- and even-numbered TM domains, 4 shorter hydrophobic helices that resemble the P-loops of K+ channels (14, 27, 55). In the K+ channel, these pore-forming loops end in the filter residues glycine-tyrosine-glycine, which coordinate K+ by means of their backbones’ carbonyl oxygens (13). The P-loop-like helices of Trk/HKT transporters end in a single conserved glycine (48), and these glycines have been shown to determine K+ selectivity over Na+ of the transporters (34, 49). Thus, a Trk/HKT monomer with 8 TM domains and 4 P-loops is thought to have a similar pore architecture to a K+ channel tetramer with two TM domains and one P-loop per subunit. The Trk/HKT transporters are important for cellular K+ acquisition in microorganisms, since trk null mutant yeast or bacteria exhibit growth phenotypes on media containing low K+ concentrations (20, 46). The roles of the Trk/HKT transporters in plants are more diverse, including Na+ distribution (10, 33, 47), osmoregulation (32), and salt tolerance (39). So far, no HKT/Trk transporter has been described from the metazoa or protista.Trypanosoma brucei subsp. parasites comprise the causative agents of human and livestock trypanosomosis: sleeping sickness and nagana, respectively. The distribution of the parasites is restricted by that of their vector, the blood-sucking tsetse fly (Glossina spp.), to the so-called tsetse belt comprising 36 countries between the Sahara desert and the Kalahari (3, 8). African trypanosomes proliferate extracellularly in the blood, evading the mammalian immune response by antigenic variation. Untreated sleeping sickness is fatal. There is an urgent need for new and better drugs since the current ones, the arsenical melarsoprol in particular, suffer from severe side effects (31). In the mammalian bloodstream, the parasites encounter a rich and steady supply of nutrients, readily imported by specific permeases or endocytosed via receptors (7). Research on trypanosomal nutrient uptake has so far concentrated on transporters of organic substrates: nucleobases, nucleosides, sugars, and amino acids (4, 12, 26, 30, 35, 56). Little is known about how the parasites import inorganic nutrients. The malaria parasite Plasmodium falciparum possesses two putative K+ channel subunits with 6 TM domains and one P-loop (19, 52). Disruption of an orthologous gene in Plasmodium berghei strongly impaired the development of the malaria parasites in the mosquito (18). However, these putative channels have not yet been proven to be permeable to K+. The T. brucei genome (6) is annotated to contain two putative K+ channels; in addition, a putative ATPase has been identified resembling fungal Na+/K+ efflux ATPases (5, 45). None of these has been addressed experimentally. Here we present the identification and characterization of TbHKT1 (Tb10.70.2940), a Trk/HKT-type K+ transporter from Trypanosoma brucei and representative of a new clade of Trk/HKT genes from kinetoplastid parasites. 相似文献
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Vodnala M Fijolek A Rofougaran R Mosimann M Mäser P Hofer A 《The Journal of biological chemistry》2008,283(9):5380-5388
African sleeping sickness is caused by Trypanosoma brucei. This extracellular parasite lacks de novo purine biosynthesis, and it is therefore dependent on exogenous purines such as adenosine that is taken up from the blood and other body fluids by high affinity transporters. The general belief is that adenosine needs to be cleaved to adenine inside the parasites in order to be used for purine nucleotide synthesis. We have found that T. brucei also can salvage this nucleoside by adenosine kinase (AK), which has a higher affinity to adenosine than the cleavage-dependent pathway. The recombinant T. brucei AK (TbAK) preferably used ATP or GTP to phosphorylate both natural and synthetic nucleosides in the following order of catalytic efficiencies: adenosine > cordycepin > deoxyadenosine > adenine arabinoside (Ara-A) > inosine > fludarabine (F-Ara-A). TbAK differed from the AK of the related intracellular parasite Leishmania donovani by having a high affinity to adenosine (K m = 0.04-0.08 microm depending on [phosphate]) and by being negatively regulated by adenosine (K i = 8-14 microm). These properties make the enzyme functionally related to the mammalian AKs, although a phylogenetic analysis grouped it together with the L. donovani enzyme. The combination of a high affinity AK and efficient adenosine transporters yields a strong salvage system in T. brucei, a potential Achilles' heel making the parasites more sensitive than mammalian cells to adenosine analogs such as Ara-A. Studies of wild-type and AK knockdown trypanosomes showed that Ara-A inhibited parasite proliferation and survival in an AK-dependent manner by affecting nucleotide levels and by inhibiting nucleic acid biosynthesis. 相似文献
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SANYA D. ONABAMERO B.SC Ph.D. F.L.S. 《Zoological Journal of the Linnean Society》1957,43(290):123-133
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We describe here a new method for specific staining of mast cells using ferroin. Different hamster tissues were fixed in 4% formalin and processed for paraffin embedding. Sections were stained with hematoxylin followed by ferroin acidified with 2.5 N sulfuric acid to pH 4.0. Mast cells stained an intense orange color that contrasted markedly with bluish violet nuclei. High contrast was also observed when ferroin colored sections were counterstained with light green instead of hematoxylin. To evaluate the specificity of the stain, hamster cheek pouch sections were stained with toluidine blue, alcian blue-safranin O, and ferroin. Quantitative evaluation of mast cells stained with the three techniques showed no statistical difference. The simplicity and selectivity of this method is sufficient for image analysis of mast cells. 相似文献
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