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Transporter Proteins (transporter + protein)
Selected AbstractsRole of the MRP1/ABCC1 Multidrug Transporter Protein in CancerIUBMB LIFE, Issue 12 2007Marcia Munoz Abstract Multidrug resistance is a major obstacle to cancer treatment and leads to poor prognosis for the patient. Multidrug resistance-associated protein 1 (MRP1) transports a wide range of therapeutic agents as well as diverse physiological substrates and may play a role in the development of drug resistance in several cancers including those of the lung, breast and prostate, as well as childhood neuroblastoma. The majority of patients with neuroblastoma present with widely disseminated disease at diagnosis and despite intensive treatment, the prognosis for such patients is dismal. There is increasing evidence that MRP1 is a MYCN target gene involved in the development of multidrug resistance in neuroblastoma. Given the importance of MRP1 overexpression in neuroblastoma, MRP1 inhibition may be a clinically relevant approach to improving patient outcome in this disease. [source] Molecular Recognition in Partially Folded States of a Transporter Protein: Temperature-dependent Specificity of Bovine Serum AlbuminPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2008Debapriya Banerjee The specificity of molecular recognition of a transporter protein bovine serum albumin (BSA) in its different partially folded states has been studied. In order to avoid complications due to chemical denaturation, we have prepared thermally induced partially folded states of the protein. The partially folded states have been structurally characterized by circular dichroism and differential thermal analysis techniques. The change in the globular structure of the protein as a consequence of thermal unfolding has also been characterized by dynamic light scattering. Steady state, picosecond-resolved fluorescence and polarization gated spectroscopies on the ligands (DCM, LDS 750) in the protein reveal the dynamics of the binding sites and the specificity of ligand binding of BSA. Picosecond resolved Förster resonance energy transfer studies on the donor DCM and acceptor LDS 750 confirm that the specificity of ligand binding in the binding site is maintained up to 70°C. At 75°C, the protein loses its specificity of recognition at the aforesaid site. [source] The mode of action of thiazolidinediones,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Hans Hauner Abstract The thiazolidinediones (TZDs) or ,glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR,), a nuclear receptor. TZD-induced activation of PPAR, alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR, is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-, (TNF-,), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full ,insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease. Copyright © 2002 John Wiley & Sons, Ltd. [source] Aly/,REF, a factor for mRNA transport, activates RH gene promoter functionFEBS JOURNAL, Issue 11 2005Hiroshi Suganuma The rhesus (Rh) blood group antigens are of considerable importance in transfusion medicine as well as in newborn or autoimmune hemolytic diseases due to their high antigenicity. We identified a major DNaseI hypersensitive site at the 5, flanking regions of both RHD and RHCE exon 1. A 34 bp fragment located at ,191 to ,158 from a translation start position, and containing the TCCCCTCCC sequence, was involved in enhancing promoter activity, which was assessed by luciferase reporter gene assay. A biotin-labelled 34 bp probe isolated an mRNA transporter protein, Aly/REF. The specific binding of Aly/REF to RH promoter in erythroid was confirmed by chromatin immunoprecipitation assay. The silencing of Aly/REF by siRNA reduced not only the RH promoter activity of the reporter gene but also transcription from the native genome. These facts provide second proof of Aly/REF as a transcription coactivator, initially identified as a coactivator for the TCR, enhancer function. Aly/REF might be a novel transcription cofactor for erythroid-specific genes. [source] Human and Drosophila UDP-galactose transporters transport UDP- N -acetylgalactosamine in addition to UDP-galactoseFEBS JOURNAL, Issue 1 2002Hiroaki Segawa A putative Drosophila nucleotide sugar transporter was characterized and shown to be the Drosophila homologue of the human UDP-Gal transporter (hUGT). When the Drosophila melanogaster UDP-Gal transporter (DmUGT) was expressed in mammalian cells, the transporter protein was localized in the Golgi membranes and complemented the UDP-Gal transport deficiency of Lec8 cells but not the CMP-Sia transport deficiency of Lec2 cells. DmUGT and hUGT were expressed in Saccharomyces cerevisiae cells in functionally active forms. Using microsomal vesicles isolated from Saccharomyces cerevisiae expressing these transporters, we unexpectedly found that both hUGT and DmUGT could transport UDP-GalNAc as well as UDP-Gal. When amino-acid residues that are conserved among human, murine, fission yeast and Drosophila UGTs, but are distinct from corresponding ones conserved among CMP-Sia transporters (CSTs), were substituted by those found in CST, the mutant transporters were still active in transporting UDP-Gal. One of these mutants in which Asn47 was substituted by Ala showed aberrant intracellular distribution with concomitant destabilization of the protein product. However, this mutation was suppressed by an Ile51 to Thr second-site mutation. Both residues were localized within the first transmembrane helix, suggesting that the structure of the helix contributes to the stabilization and substrate recognition of the UGT molecule. [source] Serotonin Transporter Protein Polymorphism and Harm Avoidance Personality in Migraine without AuraHEADACHE, Issue 6 2006Jeong Wook Park MD Objective.,To investigate polymorphisms in the serotonin transporter protein gene and harm avoidance personality dimension in patients with migraine without aura (MWOA). Background.,The serotonin transporter protein is a key modulator of serotonergic synaptic neurotransmission. Two polymorphic regions of the gene for serotonin transporter protein have been found, and are associated with variations in the functional activity of serotonin caused by differing transcriptional efficiency. The harm avoidance (HA) personality trait may also be heritable and associated with altered serotonergic neurotransmitter activity. Design.,We amplified the polymorphism in the promoter of serotonin transporter protein (5-HTTLPR) and the variable number of tandem repeats polymorphism within intron 2 (VNTR) using the polymerase chain reaction and performed genotype polymorphism analyses in 97 patients with MWOA and 100 healthy controls. We investigated serotonin-related personality traits by evaluating the HA personality dimension using a tridimensional questionnaire. Results.,The genotype frequencies and allele distributions of 5-HTTLPR did not differ between patients with MWOA and controls. The VNTR genotype STin2.12/STin2.12 was significantly more common in patients with MWOA (90%) than in controls (77%; P= .017). Patients with MWOA also had HA scores (21.9 ± 6.4) significantly higher than those of controls (16.3 ± 6.1; P < .001). Conclusions.,Serotonergic activity might be involved in the development of MWOA and VNTR of serotonin transporter gene might be one of the genetically contributing factors. [source] Towards an understanding of organic anion transporters: Structure,function relationshipsMEDICINAL RESEARCH REVIEWS, Issue 6 2004Guofeng You Abstract Organic anion transporters (OAT) play essential roles in the body disposition of clinically important anionic drugs, including anti-viral drugs, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. The activities of OATs are directly linked to drug toxicity and drug,drug interactions. So far, four members of the OAT family have been identified: OAT1, OAT2, OAT3, and OAT4. These transporters share several common structural features including 12 transmembrane domains, multiple glycosylation sites localized in the first extracellular loop between transmembrane domains 1 and 2, and multiple phosphorylation sites present in the intracellular loop between transmembrane domains 6 and 7, and in the carboxyl terminus. The impact of these structural features on the function of these transporters has just begun to be explored. In the present review, the author will summarize recent progress made from her laboratory as well as from others, on the molecular characterization of the structure,function relationships of OATs, including particular amino acid residues/regions of the transporter protein ("molecular domains") that potentially determine transport characteristics. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 6, 762,774, 2004 [source] Creatine transporter and mitochondrial creatine kinase protein content in myopathiesMUSCLE AND NERVE, Issue 5 2001M.A. Tarnopolsky MD Abstract Total creatine or phosphocreatine, or both, are reduced in the skeletal muscle of patients with inflammatory myopathy, mitochondrial myopathy, and muscular dystrophy/congenital myopathy. We used Western blotting techniques to measure skeletal muscle creatine transporter protein and sarcomeric mitochondrial creatine kinase (mtCK) protein content in patients with inflammatory myopathy (N = 8), mitochondrial myopathy (N = 5), muscular dystrophy (N = 7), and congenital myopathy (N = 3), as compared to a control group without a neuromuscular diagnosis (N = 8). Creatine transporter protein content was lower for all groups compared to control subjects (P < 0.05; P < 0.01 for congenital myopathy). Mitochondrial CK (mtCK) was lower for inflammatory myopathy (P < 0.05), higher for mitochondrial myopathy (P < 0.05), not different for muscular dystrophy, and markedly lower for the congenital myopathy group (P < 0.01), compared to control subjects. Together, these data suggest that the reduction in total creatine or phosphocreatine in patients with certain myopathies is correlated with creatine transporter and not mtCK protein content. This further supports the belief that creatine monohydrate supplementation may benefit patients with low muscle creatine stores, although the reduction in creatine transporter protein may have implications for dosing. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 682,688, 2001 [source] Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cellsCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2001J. Blumentrath Abstract Both 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (ATRA) are active metabolites of vitamin A (retinol). There exists an interaction between retinoid receptors and peroxisome proliferator-activated receptors (PPAR,). To define their functions in an insulin secreting system the effects of ATRA, 9cRA and the PPAR, agonist rosiglitazone on cell proliferation, insulin release and glucose transporter (GLUT) 2 of INS-1 cells were tested. Retinoic acid receptor (RAR-, and -,) and retinoid X receptor (RXR-, and -,) proteins are present (immunoblots). Both 9cRA and ATRA inhibit INS-1 cell proliferation ([3H]-thymidine assay) in a concentration dependent manner. Both 9cRA and ATRA increased insulin release, but only ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48,h. The insulinotropic effect of one compound is not significantly superimposed by the other indicating that the same binding sites are used by 9cRA and ATRA. The acute and chronic effects of the PPAR, agonist rosiglitazone on insulin release were additionally determined since glitazones act as transcription factors together with RXR agonists. At high concentrations (100,,m) rosiglitazone inhibited glucose (8.3,mm) stimulated insulin secretion (acute experiment over 60,min). Insulin secretion, however, was increased during a 24,h treatment at a concentration of 10,,m and again inhibited at 100,,m. Changes in preproinsulin mRNA expression were not observed. Rosiglitazone (100,,m) increased GLUT 2 mRNA paralleled by an increase of GLUT 2 protein, but only after 24,h of treatment. This data indicate that RAR and RXR mediate insulin release. The changes in GLUT 2 have no direct impact on insulin release; the inhibition seen at high concentrations of either compound is possibly the result of the observed inhibition of cell proliferation. Effects of rosiglitazone on preproinsulin mRNA and GLUT 2 (mRNA and protein) do not play a role in modulating insulin secretion. With the presence of an RXR receptor agonist the effect of rosiglitazone on insulin release becomes stimulatory. Thus the effects of RAR-, RXR agonists and rosiglitazone depend on their concentrations, the duration of their presence and are due to specific interactions. Copyright © 2001 John Wiley & Sons, Ltd. [source] MDMA, methamphetamine and their combination: possible lessons for party drug users from recent preclinical researchDRUG AND ALCOHOL REVIEW, Issue 1 2007KELLY J. CLEMENS Abstract The substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, ,Ecstasy') and methamphetamine (METH, ,ice', ,speed') are increasingly popular drugs amongst party-drug users. Studies with humans have investigated the acute and possible long-term adverse effects of these drugs, yet outcomes of such studies are often ambiguous due to a variety of confounding factors. Studies employing animal models have value in determining the acute and long-term effects of MDMA and METH on brain and behaviour. Self-administration studies show that intravenous METH is a particularly potent reinforcer in rats and other species. In contrast, MDMA appears to have powerful effects in enhancing social behaviour in laboratory animals. Brief exposure to MDMA or METH may produce long-term reductions in dopamine, serotonin and noradrenaline in the brain and alterations in the density of various receptor and transporter proteins. However it is still unclear, particularly in the case of MDMA, whether this reflects a ,neurotoxic' effect of the drug. Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies. Recent laboratory studies suggest that MDMA/METH combinations may produce greater adverse neurochemical and behavioural effects than either drug alone. This is of some concern given recent evidence that party drug users may be frequently exposed to this combination of drugs. [source] Nucleoside transporter and nucleotide vesicular transporter: Two examples of mnemonic regulationDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Raquel P. Sen Abstract According to their relevant roles in the regulation and availability of extracellular levels of purinergic signals, the nucleoside transporter and the nucleotide vesicular transporter are subject to acute regulation. The plasma membrane nucleoside transporter has been shown to exhibit several regulatory mechanisms, such as regulation by long-term signals, phosphorylation/dephosphorylation processes, and allosteric modulation. The present work reviews studies concerning allosteric modulation of nucleoside and nucleotide vesicular transporters, as the first reported examples of mnemonic behavior in transporter proteins, presenting kinetic and allosteric cooperativity. This fact implies that the protein can exhibit different conformations, each one with specific kinetic parameters. Transport substrates are able to induce slow conformational changes between the different forms of the transporter. This kinetic mechanism can provide several physiological advantages, since it allows strict control of transport capacity by changes in substrate concentrations. This allosteric modulation has been confirmed in several experimental models, the nucleoside transporter in chromaffin and endothelial cells from adrenal medulla and the nucleotide vesicular transporter in the chromaffin cell granules and rat brain synaptic vesicles. Taking into account these considerations, the mnemonic regulation described here could be a widespread mechanism among transporter proteins. Drug Dev. Res. 52:11,21, 2001. © 2001 Wiley-Liss, Inc. [source] Microarray analysis suggests the involvement of proteasomes, lysosomes, and matrix metalloproteinases in the response of motor neurons to root avulsionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2002Jian Hu Abstract We used microarray analysis of RNA expression from punch samples from ventral horn of spinal cord to identify alterations in gene expression in motor neurons 3 days after proximal spinal root avulsion, a traumatic injury that results in the death of 80% of the motor neurons. This analysis identified the anticipated increases in expression of genes coding for proteins involved in the apoptosis cascades and abortive cell cycle re-entry, as well as decreases in expression of genes coding for proteins related to neuronal functional activity, including groups of genes related to energy metabolism, transporter proteins, ion channels, and receptors. It was also found that cathepsins, metalloproteinases, and proteasome-related protein products were highly up-regulated in motor neurons following axotomy. Each of these products represent pathways that have been implicated in other models of neuronal damage, but which have not previously been described as a response to axotomy. [source] Modulation of sinusoidal and canalicular elimination of bilirubin-glucuronides by rifampicin and other cholestatic drugs in a sandwich culture of rat hepatocytesHEPATOLOGY RESEARCH, Issue 3 2008György Lengyel Aim:, Drug-induced hyperbilirubinemia has been shown to often be derived from modulation of the expression and activity of hepatobiliary transporters. In this study we examined the interactions of some therapeutic agents, which have been shown to cause cholestasis, with the elimination of bilirubin-glucuronides, in order to clarify whether these drugs modify the activity of Mrp2 and Mrp3 directly. Methods:, The modulation of bilirubin-glucuronide elimination with rifampicin, probenecid, indomethacin and benzbromarone was assayed in sandwich cultured rat hepatocytes. Results:, All the drugs studied decreased the canalicular transport, but modified the sinusoidal efflux differently. Rifampicin and probenecid stimulated the sinusoidal efflux, shifting the elimination of bilirubin-glucuronides to the sinusoidal domain (biliary excretion index: 3.9 ± 1.2; 22.7 ± 7.4 vs. 56.6 ± 1.5 and 56.8 ± 5.5). However, the overall elimination of bilirubin-glucuronides did not change significantly. In contrast, indomethacin and benzbromarone inhibited bothtransport processes, resulting in the decrease of the overall bilirubin-glucuronide elimination (61 ± 22; 56 ± 5% of the control). Rifampicin, indomethacin and benzbromarone decreased 5,(6)-carboxy-2,,7,-dichlorofluorescein transport by multidrug resistance-associated protein (Mrp)2 as visualized by confocal laser microscopy and in vesicular transport experiments. Interestingly, rifampicin decreased the MRP3 activity in vesicular transport experiments using 17-beta-estradiol-17-beta-D-glucuronide as substrate, in contrast to that observed in bilirubin-glucuronide transport experiments. Conclusion:, Here we show that the interactions of drugs on hepatobiliary transporter proteins may be identified in vitro in a sandwich culture of hepatocytes, in which canalicular and sinusoidal transport can be studied separately. [source] Polymorphism of LMP2, TAP1, LMP7 and TAP2 in Brazilian Amerindians and Caucasoids: implications for the evolution of allelic and haplotypic diversityINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2000F. Rueda Faucz In the class II region of the major histocompatibility complex (MHC), four genes implicated in processing of MHC class I-presented antigens have been described. Two of these (TAP1 and TAP2) code for endoplasmic reticulum membrane transporter proteins and the other two (LMP2 and LMP7) for proteasome subunits. These genes are polymorphic, although much less so than classical MHC class I and II genes. There is controversy concerning the possible functional implications of this variation. Population genetics is one of the means of investigating the evolutionary and functional significance of genetic polymorphisms; however, few populations have been analysed with respect to TAP and LMP diversity. We present here the polymorphism of TAP1, TAP2, LMP2 and LMP7 genes in the Kaingang and Guarani Amerindian tribes, and in the Caucasoid population of the Brazilian State of Paraná. Allele frequencies found in the Caucasoids were close to those described for similar populations. Amerindians had a somewhat more restricted polymorphism, and allele and haplotype frequencies differed greatly between the two tribes. Overall linkage disequilibrium (LD) between the four genes was low in the Caucasoids, but high in the Amerindians, for which significant LD was seen for all informative pairs of loci. Comparing results of this and previous studies we observed that, whenever significant LD occurs in non-Amerindians, it tends to be similar in the different ethnic groups. While this might be interpreted as evidence of co-evolution of genes in the TAP-LMP region, the high haplotypic diversity in all populations and low LD in non-Amerindians indicate absence of co-evolution of the different genes. Distributions of allele and genotype frequencies are consistent with the hypothesis of selective neutrality. We conclude that genetic polymorphism of the human TAP and LMP genes and haplotypes is of little, if any, functional significance. [source] ASSESSING ABSORBABILITY OF BIOACTIVE COMPONENTS IN ALOE USING IN VITRO DIGESTION MODEL WITH HUMAN INTESTINAL CELLJOURNAL OF FOOD BIOCHEMISTRY, Issue 2 2010SOON-MI SHIM ABSTRACT This study used a simulated in vitro digestion model coupled with caco-2 cell to assess the digestive stability and absorption of aloin, aloe-emodin and aloenin A. Aloenin A and aloe-emodin were stable and entirely recovered during simulated digestion, but 50% of aloin was lost. Approximately 53.2, 7.3 and 28.7% of aloe-emodin, aloenin A and aloin, respectively, was transported into both apical and basolateral compartments after 1 h incubation in caco-2 cell. The involvement of several transporter proteins for aloin and aloenin A was examined. An inhibitor of SGLT1 on apical surface (phloridzin) or that of GLUT2 on basolateral membrane (cytochalasin B) reduced the absorption of aloin by 40 or 60%, respectively, indicating that aloin is likely to be a partial substrate of SGLT1. In the presence of an efflux transporter inhibitor (verapamil), the transport of aloenin A through an intentinal apical membrane increased up to 2.1 times compared with the control (without verapamil). PRACTICAL APPLICATIONS Our results on both digestive stability and intestinal absorption characteristics of bioactive components in aloe could be of helpful information for promoting its bioavailability. The in vitro technique described in this study provides a rapid and cost-effective alternative for predicting bioavailability of biomarkers in aloe functional food. [source] The in vivo neuron-to-astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulationJOURNAL OF NEUROCHEMISTRY, Issue 2009Silvia Mangia Abstract Functional magnetic resonance spectroscopy (fMRS) allows the non-invasive measurement of metabolite concentrations in the human brain, including changes induced by variations in neurotransmission activity. However, the limited spatial and temporal resolution of fMRS does not allow specific measurements of metabolites in different cell types. Thus, the analysis of fMRS data in the context of compartmentalized metabolism requires the formulation and application of mathematical models. In the present study we utilized the mathematical model introduced by Simpson et al. (2007) to gain insights into compartmentalized metabolism in vivo from the fMRS data obtained in humans at ultra high magnetic field by Mangia et al. (2007a). This model simulates brain glucose and lactate levels in a theoretical cortical slice. Using experimentally determined concentrations and catalytic activities for the respective transporter proteins, we calculate inflow and export of glucose and lactate in endothelium, astrocytes, and neurons. We then vary neuronal and astrocytic glucose and lactate utilization capacities until close correspondence is observed between in vivo and simulated glucose and lactate levels. The results of the simulations indicate that, when literature values of glucose transport capacity are utilized, the fMRS data are consistent with export of lactate by neurons and import of lactate by astrocytes, a mechanism that can be referred to as a neuron-to-astrocyte lactate shuttle. A shuttle of lactate from astrocytes to neurons could be simulated, but this required the astrocytic glucose transport capacity to be increased by 12-fold, and required that neurons not respond to activation with increased glycolysis, two conditions that are not supported by current literature. [source] Possible therapeutic benefits of adenosine-potentiating drugs in reducing age-related degenerative disease in dogs and catsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2003R. J. Scaramuzzi Adenosine is a ubiquitous, biologically important molecule that is a precursor of other biologically active molecules. It also is a component of some co-factors and has distinct physiological actions in its own right. Levels are maintained by synthesis from dietary precursors and re-cycling. The daily turnover of adenosine is very high. Adenosine can act either as a hormone by binding to adenosine receptors, four adenosine receptor subtypes have been identified, and as an intracellular modulator, after transport into the cell by membrane transporter proteins. One of the principal intracellular actions of adenosine is inhibition of the enzyme phosphodiesterase. Extracellular adenosine also has specific neuromodulatory actions on dopamine and glutamate. Selective and nonselective agonists and antagonists of adenosine are available. The tasks of developing, evaluating and exploiting the therapeutic potential of these compounds is still in its infancy. Adenosine has actions in the central nervous system (CNS), heart and vascular system, skeletal muscle and the immune system and the presence of receptors suggests potential actions in the gonads and other organs. Adenosine agonists improve tissue perfusion through actions on vascular smooth muscle and erythrocyte fluidity and they can be used to improve the quality of life in aged dogs. This article reviews the therapeutic potential of adenosine-potentiating drugs in the treatment of age-related conditions in companion animals, some of which may be exacerbated by castration or spaying at an early age. [source] Genetic cholestasis, causes and consequences for hepatobiliary transportLIVER INTERNATIONAL, Issue 5 2003Peter L. M. Jansen Abstract: Bile salts take part in an efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver, the sodium-dependent taurocholate transporter at the basolateral (sinusoidal) membrane and the bile salt export pump at the canalicular membrane mediate hepatic uptake and hepatobiliary secretion of bile salts. Canalicular secretion is the driving force for the enterohepatic cycling of bile salts and most genetic diseases are caused by defects of canalicular secretion. Impairment of bile flow leads to adaptive changes in the expression of transporter proteins and enzymes of the cytochrome P-450 system involved in the metabolism of cholesterol and bile acids. Bile salts act as ligands for transcription factors. As such, they stimulate or inhibit the transcription of genes encoding transporters and enzymes involved in their own metabolism. Together these changes appear to serve mainly a hepatoprotective function. Progressive familial intrahepatic cholestasis (PFIC) results from mutations in various genes encoding hepatobiliary transport proteins. Mutations in the FIC1 gene cause relapsing or permanent cholestasis. The relapsing type of cholestasis is called benign recurrent intrahepatic cholestasis, the permanent type of cholestasis PFIC type 1. PFIC type 2 results from mutations in the bile salt export pump (BSEP) gene. This is associated with permanent cholestasis since birth. Serum gamma-glutamyltransferase (gamma-GT) activity is low to normal in PFIC types 1 and 2. Bile diversion procedures, causing a decreased bile salt pool, have a beneficial effect in a number of patients with these diseases. However, liver transplantation is often necessary. PFIC type 3 is caused by mutations in the MDR3 gene. MDR3 is a phospholipid translocator in the canalicular membrane. Because of the inability to secrete phospholipids, patients with PFIC type 3 produce bile acid-rich toxic bile that damages the intrahepatic bile ducts. Serum gamma-GT activity is elevated in these patients. Ursodeoxycholic acid therapy is useful for patients with a partial defect. Liver transplantation is a more definitive therapy for these patients. [source] The sugar porter gene family of Laccaria bicolor: function in ectomycorrhizal symbiosis and soil-growing hyphaeNEW PHYTOLOGIST, Issue 2 2008Mónica Fajardo López Summary ,,Formation of ectomycorrhizas, a symbiosis with fine roots of woody plants, is one way for soil fungi to overcome carbohydrate limitation in forest ecosystems. ,,Fifteen potential hexose transporter proteins, of which 10 group within three clusters, are encoded in the genome of the ectomycorrhizal model fungus Laccaria bicolor. For 14 of them, transcripts were detectable. ,,When grown in liquid culture, carbon starvation resulted in at least twofold higher transcript abundances for seven genes. Temporarily elevated transcript abundance after sugar addition was observed for three genes. Compared with the extraradical mycelium, ectomycorrhiza formation resulted in a strongly enhanced expression of six genes, of which four revealed their highest observed transcript abundances in symbiosis. A function as hexose importer was proven for three of them. Only three genes, of which just one was expressed at a considerable level, revealed a reduced transcript content in mycorrhizas. ,,From gene expression patterns and import kinetics, the L. bicolor hexose transporters could be divided into two groups: those responsible for uptake of carbohydrates by soil-growing hyphae, for improved carbon nutrition, and to reduce nutrient uptake competition by other soil microorganisms; and those responsible for efficient hexose uptake at the plant,fungus interface. [source] Docking and homology modeling explain inhibition of the human vesicular glutamate transportersPROTEIN SCIENCE, Issue 9 2007Jonas Almqvist Abstract As membrane transporter proteins, VGLUT1,3 mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. This function is crucial for exocytosis and the role of glutamate as the major excitatory neurotransmitter in the central nervous system. The three transporters, sharing 76% amino acid sequence identity in humans, are highly homologous but differ in regional expression in the brain. Although little is known regarding their three-dimensional structures, hydropathy analysis on these proteins predicts 12 transmembrane segments connected by loops, a topology similar to other members in the major facilitator superfamily, where VGLUT1,3 have been phylogenetically classified. In this work, we present a three-dimensional model for the human VGLUT1 protein based on its distant bacterial homolog in the same superfamily, the glycerol-3-phosphate transporter from Escherichia coli. This structural model, stable during molecular dynamics simulations in phospholipid bilayers solvated by water, reveals amino acid residues that face its pore and are likely to affect substrate translocation. Docking of VGLUT1 substrates to this pore localizes two different binding sites, to which inhibitors also bind with an overall trend in binding affinity that is in agreement with previously published experimental data. [source] GIGANTEA is a component of a regulatory pathway determining wall ingrowth deposition in phloem parenchyma transfer cells of Arabidopsis thalianaTHE PLANT JOURNAL, Issue 4 2010Joshua Edwards Summary Transfer cells are specialised transport cells containing invaginated wall ingrowths that generate an amplified plasma membrane surface area with high densities of transporter proteins. They trans -differentiate from differentiated cells at sites at which enhanced rates of nutrient transport occur across apo/symplasmic boundaries. Despite their physiological importance, little is known of the molecular mechanisms regulating construction of their intricate wall ingrowths. We investigated the genetic control of wall ingrowth formation in phloem parenchyma transfer cells of leaf minor veins in Arabidopsis thaliana. Wall ingrowth development in these cells is substantially enhanced upon exposing plants to high-light or cold treatments. A hierarchical bioinformatic analysis of public microarray datasets derived from the leaves of plants subjected to these treatments identified GIGANTEA (GI) as one of 46 genes that are commonly up-regulated twofold or more under both high-light and cold conditions. Histological analysis of the GI mutants gi-2 and gi-3 showed that the amount of phloem parenchyma containing wall ingrowths was reduced 15-fold compared with wild-type. Discrete papillate wall ingrowths were formed in gi-2 plants but failed to develop into branched networks. Wall ingrowth development in gi-2 was not rescued by exposing these plants to high-light or cold conditions. In contrast, over-expression of GI in the gi-2 background restored wall ingrowth deposition to wild-type levels. These results indicate that GI regulates the ongoing development of wall ingrowth networks at a point downstream of inputs from environmental signals. [source] The characterization of novel mycorrhiza-specific phosphate transporters from Lycopersicon esculentum and Solanum tuberosum uncovers functional redundancy in symbiotic phosphate transport in solanaceous speciesTHE PLANT JOURNAL, Issue 2 2005Réka Nagy Summary Solanaceous species are among the >200 000 plant species worldwide forming a mycorrhiza, that is, a root living in symbiosis with soil-borne arbuscular-mycorrhizal (AM) fungi. An important parameter of this symbiosis, which is vital for ecosystem productivity, agriculture, and horticulture, is the transfer of phosphate (Pi) from the AM fungus to the plant, facilitated by plasma membrane-spanning Pi transporter proteins. The first mycorrhiza-specific plant Pi transporter to be identified, was StPT3 from potato [Nature414 (2004) 462]. Here, we describe novel Pi transporters from the solanaceous species tomato, LePT4, and its orthologue StPT4 from potato, both being members of the Pht1 family of plant Pi transporters. Phylogenetic tree analysis demonstrates clustering of both LePT4 and StPT4 with the mycorrhiza-specific Pi transporter from Medicago truncatula [Plant Cell, 14 (2002) 2413] and rice [Proc. Natl Acad. Sci. USA, 99 (2002) 13324], respectively, but not with StPT3, indicating that two non-orthologous mycorrhiza-responsive genes encoding Pi transporters are co-expressed in the Solanaceae. The cloned promoter regions from both genes, LePT4 and StPT4, exhibit a high degree of sequence identity and were shown to direct expression exclusively in colonized cells when fused to the GUS reporter gene, in accordance with the abundance of LePT4 and StPT4 transcripts in mycorrhized roots. Furthermore, extensive sequencing of StPT4 -like clones and subsequent expression analysis in potato and tomato revealed the presence of a close paralogue of StPT4 and LePT4, named StPT5 and LePT5, respectively, representing a third Pi transport system in solanaceous species which is upregulated upon AM fungal colonization of roots. Knock out of LePT4 in the tomato cv. MicroTom indicated considerable redundancy between LePT4 and other Pi transporters in tomato. [source] Organic and inorganic anions in Shiraz and Chardonnay grape berries and wine as affected by rootstock under saline conditionsAUSTRALIAN JOURNAL OF GRAPE AND WINE RESEARCH, Issue 1 2010H. GONG Abstract Background and Aims:, Rootstocks influence the inorganic ion and organic acid composition of grapes of the scion variety. The aim was to investigate the impact of rootstocks on the inter-relationship of inorganic ions and organic acid anions in the skin and pulp of grapes and in resultant wine. Methods and Results:, Vines were irrigated with water having electrical conductivities in the range 1.6,2.1 dS/m. Chloride, sodium, potassium, malic and tartaric acid concentrations were higher in almost all cases in skin than in pulp. Significant positive correlations existed between chloride and sodium concentrations in both pulp and skin. A significant negative linear regression existed between malic acid and both chloride and sodium concentrations in skin of Chardonnay berries. There were positive linear regressions in chloride concentration between berry (pulp and skin) and resultant wine chloride in both Chardonnay and Shiraz. Conclusion:, The higher malic acid and lower chloride concentrations in skin of most grafted Chardonnay and Shiraz vines, and vice versa for own rooted vines, may indicate competition for similar transporter proteins involved in loading into skins. Alternatively, higher salt concentrations in skins may be associated with accelerated malic acid catabolism. Significance of the Study:, Chloride-excluding rootstocks demonstrated advantages through reduced chloride (but not sodium) in pulp and skin of grape berries and in resultant wines. Where rootstocks reduced chloride concentrations in skin of grape berries, there is potential for higher malic acid in skin and in the resultant red wines. [source] Neurotransmitter transporters and their impact on the development of psychopharmacologyBRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2006Leslie Iversen The synaptic actions of most neurotransmitters are inactivated by reuptake into the nerve terminals from which they are released, or by uptake into adjacent cells. A family of more than 20 transporter proteins is involved. In addition to the plasma membrane transporters, vesicular transporters in the membranes of neurotransmitter storage vesicles are responsible for maintaining vesicle stores and facilitating exocytotic neurotransmitter release. The cell membrane monoamine transporters are important targets for CNS drugs. The transporters for noradrenaline and serotonin are key targets for antidepressant drugs. Both noradrenaline-selective and serotonin-selective reuptake inhibitors are effective against major depression and a range of other psychiatric illnesses. As the newer drugs are safer in overdose than the first-generation tricyclic antidepressants, their use has greatly expanded. The dopamine transporter (DAT) is a key target for amphetamine and methylphenidate, used in the treatment of attention deficit hyperactivity disorder. Psychostimulant drugs of abuse (amphetamines and cocaine) also target DAT. The amino-acid neurotransmitters are inactivated by other families of neurotransmitter transporters, mainly located on astrocytes and other non-neural cells. Although there are many different transporters involved (four for GABA; two for glycine/D -serine; five for L -glutamate), pharmacology is less well developed in this area. So far, only one new amino-acid transporter-related drug has become available: the GABA uptake inhibitor tiagabine as a novel antiepileptic agent. British Journal of Pharmacology (2006) 147, S82,S88. doi:10.1038/sj.bjp.0706428 [source] | |||||||||||||||||||||||||