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Transporter Family (transporter + family)
Selected AbstractsTransport-dependent endocytosis and turnover of a uric acid-xanthine permeaseMOLECULAR MICROBIOLOGY, Issue 1 2010Christos Gournas Summary In this work we unmask a novel downregulation mechanism of the uric acid/xanthine transporter UapA, the prototype member of the ubiquitous Nucleobase-Ascorbate Transporter family, directly related to its function. In the presence of substrates, UapA is endocytosed, sorted into the multivesicular body pathway and degraded in vacuoles. Substrate-induced endocytosis, unlike ammonium-induced turnover, is absolutely dependent on UapA activity and several lines of evidence showed that the signal for increased endocytosis is the actual translocation of substrates through the UapA protein. The use of several UapA functional mutants with altered kinetics and specificity has further shown that transport-dependent UapA endocytosis occurs through a mechanism, which senses subtle conformational changes associated with the transport cycle. We also show that distinct mechanisms of UapA endocytosis necessitate ubiquitination of a single Lys residue (K572) by HulARsp5. Finally, we demonstrate that in the presence of substrates, non-functional UapA versions can be endocytosed in trans if expressed in the simultaneous presence of active UapA versions, even if the latter cannot be endocytosed themselves. [source] A gene repertoire for nitrogen transporters in Laccaria bicolorNEW PHYTOLOGIST, Issue 2 2008Eva Lucic Summary ,,Ectomycorrhizal interactions established between the root systems of terrestrial plants and hyphae from soil-borne fungi are the most ecologically widespread plant symbioses. The efficient uptake of a broad range of nitrogen (N) compounds by the fungal symbiont and their further transfer to the host plant is a major feature of this symbiosis. Nevertheless, we far from understand which N form is preferentially transferred and what are the key molecular determinants required for this transfer. ,,Exhaustive in silico analysis of N-compound transporter families were performed within the genome of the ectomycorrhizal model fungus Laccaria bicolor. A broad phylogenetic approach was undertaken for all families and gene regulation was investigated using whole-genome expression arrays. ,,A repertoire of proteins involved in the transport of N compounds in L. bicolor was established that revealed the presence of at least 128 gene models in the genome of L. bicolor. Phylogenetic comparisons with other basidiomycete genomes highlighted the remarkable expansion of some families. Whole-genome expression arrays indicate that 92% of these gene models showed detectable transcript levels. ,,This work represents a major advance in the establishment of a transportome blueprint at a symbiotic interface, which will guide future experiments. [source] A screen for neurotransmitter transporters expressed in the visual system of Drosophila melanogaster identifies three novel genesDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2007Rafael Romero-Calderón Abstract The fly eye provides an attractive substrate for genetic studies, and critical transport activities for synaptic transmission and pigment biogenesis in the insect visual system remain unknown. We therefore screened for transporters in Drosophila melanogaster that are down-regulated by genetically ablating the eye. Using a large panel of transporter specific probes on Northern blots, we identified three transcripts that are down-regulated in flies lacking eye tissue. Two of these, CG13794 and CG13795, are part of a previously unknown subfamily of putative solute carriers within the neurotransmitter transporter family. The third, CG4476, is a member of a related subfamily that includes characterized nutrient transporters expressed in the insect gut. Using imprecise excision of a nearby transposable P element, we have generated a series of deletions in the CG4476 gene. In fast phototaxis assays, CG4476 mutants show a decreased behavioral response to light, and the most severe mutant behaves as if it were blind. These data suggest an unforeseen role for the "nutrient amino acid transporter" subfamily in the nervous system, and suggest new models to study transport function using the fly eye. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source] Organic anion-transporting polypeptide (OATP) transporter family and drug dispositionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2003R. B. Kim Abstract Drug transporters are increasingly recognized as a key determinant of drug disposition. Recent studies have revealed that targeted expression of drug uptake and efflux transporters to specific cell membrane domains allows for the efficient directional movement of many drugs in clinical use. While the role of certain efflux transporters such as MDR1 (P-glycoprotein) in drug disposition has been extensively studied, emerging evidence suggests that uptake transporters may also be important to the intestinal absorption and renal or hepatic elimination of drugs. Members of the organic anion-transporting polypeptide (OATP) family of drug uptake transporters have been found capable of transporting a large array of structurally divergent drugs. Moreover, expression of OATP isoforms in the gastrointestinal tract, liver and kidney, as well as at the level of the blood,brain barrier, has important implications for our understanding of the factors governing drug absorption, elimination and tissue penetration. [source] The position of an arginine residue influences substrate affinity and K+ coupling in the human glutamate transporter, EAAT1JOURNAL OF NEUROCHEMISTRY, Issue 2 2010Renae M. Ryan J. Neurochem. (2010) 114, 565,575. Abstract Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and extracellular glutamate levels are controlled by a family of transporters known as excitatory amino acid transporters (EAATs). The EAATs transport glutamate and aspartate with similar micromolar affinities and this transport is coupled to the movement of Na+, K+, and H+. The crystal structure of a prokaryotic homologue of the EAATs, aspartate transporter from Pyrococcus horokoshii (GltPh), has yielded important insights into the architecture of this transporter family. GltPh is a Na+ -dependent transporter that has significantly higher affinity for aspartate over glutamate and is not coupled to H+ or K+. The highly conserved carboxy-terminal domains of the EAATs and GltPh contain the substrate and ion binding sites, however, there are a couple of striking differences in this region that we have investigated to better understand the transport mechanism. An arginine residue is in close proximity to the substrate binding site of both GltPh and the EAATs, but is located in transmembrane domain (TM) 8 in the EAATs and hairpin loop 1 (HP1) of GltPh. Here we report that the position of this arginine residue can explain some of the functional differences observed between the EAATs and GltPh. Moving the arginine residue from TM8 to HP1 in EAAT1 results in a transporter that has significantly increased affinity for both glutamate and aspartate and is K+ independent. Conversely, moving the arginine residue from HP1 to TM8 in GltPh results in a transporter that has reduced affinity for aspartate. [source] Fluoroquinolone efflux mediated by ABC transportersJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2008Ana I. Alvarez Abstract Quinolones and fluoroquinolones are broad spectrum bactericidal drugs, which are widely used in both human and veterinary medicine. These drugs can quite easily enter cells and are often used to treat intracellular pathogens. Some fluoroquinolones have been reported to undergo efflux, which could explain their low bioavailability. There is a growing need to understand resistance mechanisms to quinolones, involving for instance mutations or the action of efflux pumps. Several members of the ATP-binding cassette (ABC) drug efflux transporter family (MDR, MRP, ABCG2) significantly affect the pharmacokinetic disposition of quinolones. Active secretory mechanisms common to all fluoroquinolones have been suggested, as well as competition between fluoroquinolones at transporter sites. For grepafloxacin and its metabolites, MRP2 has been demonstrated to mediate biliary excretion. However, MDR1 is responsible for grepafloxacin intestinal secretion. Recently it has been shown that ciprofloxacin and enrofloxacin are efficiently transported ABCG2 substrates which are actively secreted into milk. It appears that multiple ABC transporters contribute to the overall secretion of fluoroquinolones. The objective of this work is to review the recent advances in insights into ABC transporters and their effects on fluoroquinolone disposition and resistance including data on drug secretion into milk. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3483,3493, 2008 [source] Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agentsMEDICINAL RESEARCH REVIEWS, Issue 4 2005Ahcène Boumendjel Abstract Multidrug resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. It is able to transport a broad range of anticancer drugs through cellular membranes, thus limiting their antiproliferative action. Since its discovery in 1992, MRP1 has been the most studied among MRP proteins, which now count nine members. Besides the biological work, which targets structure elucidation, binding sites location, and mode of action, most efforts have been focused on finding molecules which act as MRP1 inhibitors. In this review, we attempt to summarize and highlight studies dealing with modulators of MRP1-mediated multidrug resistance (MDR), which have been accomplished in the last 5 years. The reported MRP1 inhibitors are discussed according to their chemical class. Finally, we try to bring information on structure,activity relationship (SAR) aspects and how modulators might interact with MRP1. This study may facilitate the rational design of future modulators of MDR. © 2005 Wiley Periodicals, Inc. [source] Of blood, brains and bacteria, the Amt/Rh transporter family: emerging role of Amt as a unique microbial sensorMOLECULAR MICROBIOLOGY, Issue 1 2009Pier-Luc Tremblay Summary Members of the Amt/Rh family of transporters are found almost ubiquitously in all forms of life. However, the molecular state of the substrate (NH3 or NH4+) has been the subject of active debate. At least for bacterial Amt proteins, the model emerging from computational, X-ray crystal and mutational analysis is that NH4+ is deprotonated at the exterior, conducted through the membrane as NH3, and reprotonated at the cytoplasmic interface. A proton concomitantly is transferred from the exterior to the interior, although the mechanism is unclear. Here we discuss recent evidence indicating that an important function of at least some eukaryotic and bacterial Amts is to act as ammonium sensors and regulate cellular metabolism in response to changes in external ammonium concentrations. This is now well documented in the regulation of yeast pseudohyphal development and filamentous growth. As well, membrane sequestration of GlnK, a PII signal transduction protein, by AmtB has been shown to regulate nitrogenase in some diazotrophs, and nitrogen metabolism in some Gram-positive bacteria. Formation of GlnK,AmtB membrane complexes might have other, as yet undiscovered, regulatory roles. This possibility is emphasized by the discovery in some genomes of genes for chimeric Amts with fusions to various regulatory elements. [source] Managing the manganese: molecular mechanisms of manganese transport and homeostasisNEW PHYTOLOGIST, Issue 3 2005Jon K. Pittman Summary Manganese (Mn) is an essential metal nutrient for plants. Recently, some of the genes responsible for transition metal transport in plants have been identified; however, only relatively recently have Mn2+ transport pathways begun to be identified at the molecular level. These include transporters responsible for Mn accumulation into the cell and release from various organelles, and for active sequestration into endomembrane compartments, particularly the vacuole and the endoplasmic reticulum. Several transporter gene families have been implicated in Mn2+ transport, including cation/H+ antiporters, natural resistance-associated macrophage protein (Nramp) transporters, zinc-regulated transporter/iron-regulated transporter (ZRT/IRT1)-related protein (ZIP) transporters, the cation diffusion facilitator (CDF) transporter family, and P-type ATPases. The identification of mutants with altered Mn phenotypes can allow the identification of novel components in Mn homeostasis. In addition, the characterization of Mn hyperaccumulator plants can increase our understanding of how plants can adapt to excess Mn, and ultimately allow the identification of genes that confer this stress tolerance. The identification of genes responsible for Mn2+ transport has substantially improved our understanding of plant Mn homeostasis. [source] A common ABCC2 promoter polymorphism is not a determinant of the risk of spina bifida ,BIRTH DEFECTS RESEARCH, Issue 6 2004Liselotte E. Jensen Abstract BACKGROUND There is compelling evidence that the risk of spina bifida, a malformation of the caudal neural tube, is associated with maternal and/or embryonic disturbances in folate/homocysteine metabolism. Hence, functional variants of genes that influence folate/homocysteine metabolism constitute a biologically plausible group of candidate risk factors for spina bifida and other neural tube defects. One such candidate is ABCC2, the gene encoding ABCC2, (a.k.a. canalicular multispecific organic anion transporter [cMOAT], multidrug resistance related protein 2 [MRP2]), a member of the ABC transporter family that effluxes natural folates and anti-folate drugs such as methotrexate. METHODS The association between the risk of spina bifida and both the maternal and embryonic ABCC2 C(,24)T genotype was evaluated by using the transmission disequilibrium test and log-linear modeling. RESULTS These analyses provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic ABCC2 C(,24)T genotype. CONCLUSIONS The results of the present analyses suggest that the C(,24)T variant of the ABCC2 gene is not a major determinant of spina bifida risk. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc. [source] | |||||||||||||