Articles de revues : « Ion transporter »

1

Sacher, A., A. Cohen et N. Nelson. « Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes ». Journal of Experimental Biology 204, n^o 6 (15 mars 2001) : 1053–61. http://dx.doi.org/10.1242/jeb.204.6.1053.

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Transition metals are essential for many metabolic processes, and their homeostasis is crucial for life. Metal-ion transporters play a major role in maintaining the correct concentrations of the various metal ions in living cells. Little is known about the transport mechanism of metal ions by eukaryotic cells. Some insight has been gained from studies of the mammalian transporter DCT1 and the yeast transporter Smf1p by following the uptake of various metal ions and from electrophysiological experiments using Xenopus laevis oocytes injected with RNA copies (c-RNA) of the genes for these transporters. Both transporters catalyze the proton-dependent uptake of divalent cations accompanied by a ‘slippage’ phenomenon of different monovalent cations unique to each transporter. Here, we further characterize the transport activity of DCT1 and Smf1p, their substrate specificity and their transport properties. We observed that Zn(2+) is not transported through the membrane of Xenopus laevis oocytes by either transporter, even though it inhibits the transport of the other metal ions and enables protons to ‘slip’ through the DCT1 transporter. A special construct (Smf1p-s) was made to enhance Smf1p activity in oocytes to enable electrophysiological studies of Smf1p-s-expressing cells. 54Mn(2+) uptake by Smf1p-s was measured at various holding potentials. In the absence of Na(+) and at pH 5.5, metal-ion uptake was not affected by changes in negative holding potentials. Elevating the pH of the medium to 6.5 caused metal-ion uptake to be influenced by the holding potential: ion uptake increased when the potential was lowered. Na(+) inhibited metal-ion uptake in accordance with the elevation of the holding potential. A novel clutch mechanism of ion slippage that operates via continuously variable stoichiometry between the driving-force pathway (H(+)) and the transport pathway (divalent metal ions) is proposed. The possible physiological advantages of proton slippage through DCT1 and of Na(+) slippage through Smf1p are discussed.

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Agboh, Kelvin, Calvin H. F. Lau, Yvonne S. K. Khoo, Himansha Singh, Sagar Raturi, Asha V. Nair, Julie Howard et al. « Powering the ABC multidrug exporter LmrA : How nucleotides embrace the ion-motive force ». Science Advances 4, n^o 9 (septembre 2018) : eaas9365. http://dx.doi.org/10.1126/sciadv.aas9365.

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LmrA is a bacterial ATP-binding cassette (ABC) multidrug exporter that uses metabolic energy to transport ions, cytotoxic drugs, and lipids. Voltage clamping in a Port-a-Patch was used to monitor electrical currents associated with the transport of monovalent cationic HEPES+by single-LmrA transporters and ensembles of transporters. In these experiments, one proton and one chloride ion are effluxed together with each HEPES+ion out of the inner compartment, whereas two sodium ions are transported into this compartment. Consequently, the sodium-motive force (interior negative and low) can drive this electrogenic ion exchange mechanism in cells under physiological conditions. The same mechanism is also relevant for the efflux of monovalent cationic ethidium, a typical multidrug transporter substrate. Studies in the presence of Mg-ATP (adenosine 5′-triphosphate) show that ion-coupled HEPES+transport is associated with ATP-bound LmrA, whereas ion-coupled ethidium transport requires ATP binding and hydrolysis. HEPES+is highly soluble in a water-based environment, whereas ethidium has a strong preference for residence in the water-repelling plasma membrane. We conclude that the mechanism of the ABC transporter LmrA is fundamentally related to that of an ion antiporter that uses extra steps (ATP binding and hydrolysis) to retrieve and transport membrane-soluble substrates from the phospholipid bilayer.

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Mayer, Maria, Marek Dynowski et Uwe Ludewig. « Ammonium ion transport by the AMT/Rh homologue LeAMT1;1 ». Biochemical Journal 396, n^o 3 (29 mai 2006) : 431–37. http://dx.doi.org/10.1042/bj20060051.

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AMT (ammonium transporter)/Rh (Rhesus) ammonium transporters/channels are identified in all domains of life and fulfil contrasting functions related either to ammonium acquisition or excretion. Based on functional and crystallographic high-resolution structural data, it was recently proposed that the bacterial AmtB (ammonium transporter B) is a gas channel for NH3 [Khademi, O'Connell, III, Remis, Robles-Colmenares, Miercke and Stroud (2004) Science 305, 1587–1594; Zheng, Kostrewa, Berneche, Winkler and Li (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 17090–17095]. Key residues, proposed to be crucial for NH3 conduction, and the hydrophobic, but obstructed, pore were conserved in a homology model of LeAMT1;1 from tomato. Transport by LeAMT1;1 was affected by mutations of residues that were predicted to constitute the aromatic recruitment site for NH4+ at the external pore entrance. Despite the structural similarities, LeAMT1;1 was shown to transport only the ion; each transported 14C-methylammonium molecule carried a single positive elementary charge. Similarly, NH4+ (or H+/NH3) was transported, but NH3 conduction was excluded. It is concluded that related proteins and a similar molecular architecture can apparently support contrasting transport mechanisms.

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Krom, Bastiaan P., Jessica B. Warner, Wil N. Konings et Juke S. Lolkema. « Complementary Metal Ion Specificity of the Metal-Citrate Transporters CitM and CitH of Bacillus subtilis ». Journal of Bacteriology 182, n^o 22 (15 novembre 2000) : 6374–81. http://dx.doi.org/10.1128/jb.182.22.6374-6381.2000.

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ABSTRACT Citrate uptake in Bacillus subtilis is stimulated by a wide range of divalent metal ions. The metal ions were separated into two groups based on the expression pattern of the uptake system. The two groups correlated with the metal ion specificity of two homologousB. subtilis secondary citrate transporters, CitM and CitH, upon expression in Escherichia coli. CitM transported citrate in complex with Mg2+, Ni2+, Mn2+, Co2+, and Zn2+ but not in complex with Ca2+, Ba2+, and Sr2+. CitH transported citrate in complex with Ca2+, Ba2+, and Sr2+ but not in complex with Mg2+, Ni2+, Mn2+, Co2+, and Zn2+. Both transporters did not transport free citrate. Nevertheless, free citrate uptake could be demonstrated in B. subtilis, indicating the expression of at least a third citrate transporter, whose identity is not known. For both the CitM and CitH transporters it was demonstrated that the metal ion promoted citrate uptake and, vice versa, that citrate promoted uptake of the metal ion, indicating that the complex is the transported species. The results indicate that CitM and CitH are secondary transporters that transport complexes of divalent metal ions and citrate but with a complementary metal ion specificity. The potential physiological function of the two transporters is discussed.

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Beckstein, Oliver, et Fiona Naughton. « General principles of secondary active transporter function ». Biophysics Reviews 3, n^o 1 (mars 2022) : 011307. http://dx.doi.org/10.1063/5.0047967.

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Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a “driving” ion such as Na+ or H+ to the flux of the substrate. The thermodynamics of such cyclical non-equilibrium systems are well understood, and recent work has focused on the molecular mechanism of secondary active transport. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access model, is broadly recognized as the molecular framework in which to describe transporter function. However, only with the advent of high resolution crystal structures and detailed computer simulations, it has become possible to recognize common molecular-level principles between disparate transporter families. Inverted repeat symmetry in secondary active transporters has shed light onto how protein structures can encode a bi-stable two-state system. Based on structural data, three broad classes of alternating access transitions have been described as rocker-switch, rocking-bundle, and elevator mechanisms. More detailed analysis indicates that transporters can be understood as gated pores with at least two coupled gates. These gates are not just a convenient cartoon element to illustrate a putative mechanism but map to distinct parts of the transporter protein. Enumerating all distinct gate states naturally includes occluded states in the alternating access picture and also suggests what kind of protein conformations might be observable. By connecting the possible conformational states and ion/substrate bound states in a kinetic model, a unified picture emerges in which the symporter, antiporter, and uniporter functions are extremes in a continuum of functionality. As usual with biological systems, few principles and rules are absolute and exceptions are discussed as well as how biological complexity may be integrated in quantitative kinetic models that may provide a bridge from the structure to function.

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Vergara-Jaque, Ariela, Cristina Fenollar-Ferrer, Christopher Mulligan, Joseph A. Mindell et Lucy R. Forrest. « Family resemblances : A common fold for some dimeric ion-coupled secondary transporters ». Journal of General Physiology 146, n^o 5 (26 octobre 2015) : 423–34. http://dx.doi.org/10.1085/jgp.201511481.

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Membrane transporter proteins catalyze the passage of a broad range of solutes across cell membranes, allowing the uptake and efflux of crucial compounds. Because of the difficulty of expressing, purifying, and crystallizing integral membrane proteins, relatively few transporter structures have been elucidated to date. Although every membrane transporter has unique characteristics, structural and mechanistic similarities between evolutionarily diverse transporters have been identified. Here, we compare two recently reported structures of membrane proteins that act as antimicrobial efflux pumps, namely MtrF from Neisseria gonorrhoeae and YdaH from Alcanivorax borkumensis, both with each other and with the previously published structure of a sodium-dependent dicarboxylate transporter from Vibrio cholerae, VcINDY. MtrF and YdaH belong to the p-aminobenzoyl-glutamate transporter (AbgT) family and have been reported as having architectures distinct from those of all other families of transporters. However, our comparative analysis reveals a similar structural arrangement in all three proteins, with highly conserved secondary structure elements. Despite their differences in biological function, the overall “design principle” of MtrF and YdaH appears to be almost identical to that of VcINDY, with a dimeric quaternary structure, helical hairpins, and clear boundaries between the transport and scaffold domains. This observation demonstrates once more that the same secondary transporter architecture can be exploited for multiple distinct transport modes, including cotransport and antiport. Based on our comparisons, we detected conserved motifs in the substrate-binding region and predict specific residues likely to be involved in cation or substrate binding. These findings should prove useful for the future characterization of the transport mechanisms of these families of secondary active transporters.

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Lolkema, Juke S., et Dirk-Jan Slotboom. « The Hill analysis and co-ion–driven transporter kinetics ». Journal of General Physiology 145, n^o 6 (25 mai 2015) : 565–74. http://dx.doi.org/10.1085/jgp.201411332.

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Interaction of multiple ligands with a protein or protein complex is a widespread phenomenon that allows for cooperativity. Here, we review the use of the Hill equation, which is commonly used to analyze binding or kinetic data, to analyze the kinetics of ion-coupled transporters and show how the mechanism of transport affects the Hill coefficient. Importantly, the Hill analysis of ion-coupled transporters can provide the exact number of transported co-ions, regardless of the extent of the cooperativity in ion binding.

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Adelman, Joshua L., Chiara Ghezzi, Paola Bisignano, Donald D. F. Loo, Seungho Choe, Jeff Abramson, John M. Rosenberg, Ernest M. Wright et Michael Grabe. « Stochastic steps in secondary active sugar transport ». Proceedings of the National Academy of Sciences 113, n^o 27 (20 juin 2016) : E3960—E3966. http://dx.doi.org/10.1073/pnas.1525378113.

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Secondary active transporters, such as those that adopt the leucine-transporter fold, are found in all domains of life, and they have the unique capability of harnessing the energy stored in ion gradients to accumulate small molecules essential for life as well as expel toxic and harmful compounds. How these proteins couple ion binding and transport to the concomitant flow of substrates is a fundamental structural and biophysical question that is beginning to be answered at the atomistic level with the advent of high-resolution structures of transporters in different structural states. Nonetheless, the dynamic character of the transporters, such as ion/substrate binding order and how binding triggers conformational change, is not revealed from static structures, yet it is critical to understanding their function. Here, we report a series of molecular simulations carried out on the sugar transporter vSGLT that lend insight into how substrate and ions are released from the inward-facing state of the transporter. Our simulations reveal that the order of release is stochastic. Functional experiments were designed to test this prediction on the human homolog, hSGLT1, and we also found that cytoplasmic release is not ordered, but we confirmed that substrate and ion binding from the extracellular space is ordered. Our findings unify conflicting published results concerning cytoplasmic release of ions and substrate and hint at the possibility that other transporters in the superfamily may lack coordination between ions and substrate in the inward-facing state.

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9

Lolkema, Juke S., et Dirk J. Slotboom. « Models to determine the kinetic mechanisms of ion-coupled transporters ». Journal of General Physiology 151, n^o 3 (10 janvier 2019) : 369–80. http://dx.doi.org/10.1085/jgp.201812055.

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With high-resolution structures available for many ion-coupled (secondary active) transporters, a major challenge for the field is to determine how coupling is accomplished. Knowledge of the kinetic mechanism of the transport reaction, which defines the binding order of substrate and co-ions, together with the sequence with which all relevant states are visited by the transporter, will help to reveal this coupling mechanism. Here, we derived general mathematical models that can be used to analyze data from steady-state transport measurements and show how kinetic mechanisms can be derived. The models describe how the apparent maximal rate of substrate transport depends on the co-ion concentration, and vice versa, in different mechanisms. Similarly, they describe how the apparent affinity for the transported substrate is affected by the co-ion concentration and vice versa. Analyses of maximal rates and affinities permit deduction of the number of co-ions that bind before, together with, and after the substrate. Hill analysis is less informative, but in some mechanisms, it can reveal the total number of co-ions transported with the substrate. However, prior knowledge of the number of co-ions from other experimental approaches is preferred when deriving kinetic mechanisms, because the models are generally overparameterized. The models we present have wide applicability for the study of ion-coupled transporters.

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Demirbilek, Huseyin, Sonya Galcheva, Dogus Vuralli, Sara Al-Khawaga et Khalid Hussain. « Ion Transporters, Channelopathies, and Glucose Disorders ». International Journal of Molecular Sciences 20, n^o 10 (27 mai 2019) : 2590. http://dx.doi.org/10.3390/ijms20102590.

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Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi–Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.

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Venter, H., S. Shahi, L. Balakrishnan, S. Velamakanni, A. Bapna, B. Woebking et H. W. van Veen. « Similarities between ATP-dependent and ion-coupled multidrug transporters ». Biochemical Society Transactions 33, n^o 5 (26 octobre 2005) : 1008–11. http://dx.doi.org/10.1042/bst0331008.

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The movement of drugs across biological membranes is mediated by two major classes of membrane transporters. Primary-active, ABC (ATP-binding cassette) multidrug transporters are dependent on ATP-binding/hydrolysis, whereas secondary-active multidrug transporters are coupled to the proton (or sodium)-motive force that exists across the plasma membrane. Recent work on LmrA, an ABC multidrug transporter in Lactococcus lactis, suggests that primary- and secondary-active multidrug transporters share functional and structural features. Some of these similarities and their implications for the mechanism of transport by ABC multidrug transporters will be discussed.

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Nattel, Stanley, Ange Maguy, Sabrina Le Bouter et Yung-Hsin Yeh. « Arrhythmogenic Ion-Channel Remodeling in the Heart : Heart Failure, Myocardial Infarction, and Atrial Fibrillation ». Physiological Reviews 87, n^o 2 (avril 2007) : 425–56. http://dx.doi.org/10.1152/physrev.00014.2006.

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Rhythmic and effective cardiac contraction depends on appropriately timed generation and spread of cardiac electrical activity. The basic cellular unit of such activity is the action potential, which is shaped by specialized proteins (channels and transporters) that control the movement of ions across cardiac cell membranes in a highly regulated fashion. Cardiac disease modifies the operation of ion channels and transporters in a way that promotes the occurrence of cardiac rhythm disturbances, a process called “arrhythmogenic remodeling.” Arrhythmogenic remodeling involves alterations in ion channel and transporter expression, regulation and association with important protein partners, and has important pathophysiological implications that contribute in major ways to cardiac morbidity and mortality. We review the changes in ion channel and transporter properties associated with three important clinical and experimental paradigms: congestive heart failure, myocardial infarction, and atrial fibrillation. We pay particular attention to K+, Na+, and Ca2+channels; Ca2+transporters; connexins; and hyperpolarization-activated nonselective cation channels and discuss the mechanisms through which changes in ion handling processes lead to cardiac arrhythmias. We highlight areas of future investigation, as well as important opportunities for improved therapeutic approaches that are being opened by an improved understanding of the mechanisms of arrhythmogenic remodeling.

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Neverisky, Daniel L., et Geoffrey W. Abbott. « Ion channel–transporter interactions ». Critical Reviews in Biochemistry and Molecular Biology 51, n^o 4 (20 avril 2016) : 257–67. http://dx.doi.org/10.3109/10409238.2016.1172553.

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Prakash, Shraddha, Garret Cooper, Soumya Singhi et Milton H. Saier. « The ion transporter superfamily ». Biochimica et Biophysica Acta (BBA) - Biomembranes 1618, n^o 1 (décembre 2003) : 79–92. http://dx.doi.org/10.1016/j.bbamem.2003.10.010.

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Fyles, Thomas M., Tony D. James et Katharine C. Kaye. « Biomimetic ion transport : on the mechanism of ion transport by an artificial ion channel mimic ». Canadian Journal of Chemistry 68, n^o 6 (1 juin 1990) : 976–78. http://dx.doi.org/10.1139/v90-153.

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The influx of cations into vesicles mediated by a synthetic transporter is coupled to proton efflux and may be quantified by a pH-stat technique. The dependence of the transport upon cation type and concentration, upon transporter concentration, and upon temperature has been examined. The synthetic transporter is closely similar to the natural channel forming compound gramicidin, and significantly different from the carrier valinomycin, with respect to the variables examined. Keywords: ion transport, vesicle membrane, channel, gramicidin, transport mechanism.

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Zhang, Yuan-Wei, Sotiria Tavoulari, Steffen Sinning, Antoniya A. Aleksandrova, Lucy R. Forrest et Gary Rudnick. « Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT ». Proceedings of the National Academy of Sciences 115, n^o 38 (4 septembre 2018) : E8854—E8862. http://dx.doi.org/10.1073/pnas.1716870115.

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The coupled transport of ions and substrates allows transporters to accumulate substrates using the energy of transmembrane ion gradients and electrical potentials. During transport, conformational changes that switch accessibility of substrate and ion binding sites from one side of the membrane to the other must be controlled so as to prevent uncoupled movement of ions or substrates. In the neurotransmitter:sodium symporter (NSS) family, Na+stabilizes the transporter in an outward-open state, thus decreasing the likelihood of uncoupled Na+transport. Substrate binding, in a step essential for coupled transport, must overcome the effect of Na+, allowing intracellular substrate and Na+release from an inward-open state. However, the specific elements of the protein that mediate this conformational response to substrate binding are unknown. Previously, we showed that in the prokaryotic NSS transporter LeuT, the effect of Na+on conformation requires the Na2 site, where it influences conformation by fostering interaction between two domains of the protein. Here, we used cysteine accessibility to measure conformational changes of LeuT inEscherichia colimembranes. We identified a conserved tyrosine residue in the substrate binding site required for substrate to convert LeuT to inward-open states by establishing an interaction between the two transporter domains. We further identify additional required interactions between the two transporter domains in the extracellular pathway. Together with our previous work on the conformational effect of Na+, these results identify mechanistic components underlying ion–substrate coupling in NSS transporters.

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Bertelsen, Lone S., Lars Eckmann et Kim E. Barrett. « Prolonged interferon-γ exposure decreases ion transport, NKCC1, and Na+-K+-ATPase expression in human intestinal xenografts in vivo ». American Journal of Physiology-Gastrointestinal and Liver Physiology 286, n^o 1 (janvier 2004) : G157—G165. http://dx.doi.org/10.1152/ajpgi.00227.2003.

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IFN-γ is elevated in intestinal inflammation and alters barrier and transport functions in human colonic epithelial cell lines, but its effects on normal human small intestinal epithelium in vivo are poorly defined. We investigated effects of prolonged IFN-γ exposure on ion transport and expression of transporters by using human fetal small intestinal xenografts. Xenograft-bearing mice were injected with IFN-γ, and 24 h later xenografts were harvested and mounted in Ussing chambers. Baseline potential difference (PD) was not affected by IFN-γ treatment. However, conductance was enhanced and agonist-stimulated ion transport was decreased. IFN-γ also decreased expression of the Na+-K+-2Cl- cotransporter and the α-subunit of Na+-K+-ATPase compared with controls, whereas levels of the calcium-activated Cl- channel and CFTR were unaltered. Thus prolonged exposure to IFN-γ leads to decreased ion secretion due, in part, to decreased ion transporter levels. These findings demonstrate the implications of elevated IFN-γ levels in human small intestine and validate the human intestinal xenograft as a model to study chronic effects of physiologically relevant stimuli.

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Graham, D., H. Esnaud et S. Z. Langer. « Partial purification and characterization of the sodium-ion-coupled 5-hydroxytryptamine transporter of rat cerebral cortex ». Biochemical Journal 286, n^o 3 (15 septembre 1992) : 801–5. http://dx.doi.org/10.1042/bj2860801.

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A procedure for the extensive purification of the Na(+)-coupled 5-hydroxytryptamine transporter of rat cerebral cortex has been developed. The 5-hydroxytryptamine transporter was solubilized with the non-ionic detergent digitonin, and the detergent extracts were subjected to sequential affinity chromatography on a citalopram-based agarose support and wheat-germ-agglutinin-Sepharose. 5-Hydroxytryptamine transporters in the affinity-purified preparation were identified by using the selective 5-hydroxytryptamine-uptake inhibitor [3H]paroxetine, and were shown to display a similar pharmacological profile to those present in particulate preparations. An overall transporter purification of around 2000-fold was achieved with a 9% recovery. SDS/PAGE of affinity-chromatographed material starting from detergent extracts incubated in the presence or absence of 1 mM-citalopram indicated that a polypeptide of M(r) 73,000 corresponded to the 5-hydroxytryptamine-transporter protein.

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Deng, Zilin, Yingying Zhao, Zhiyuan Ma, Minglin Zhang, Hu Wang, Zhiqiang Yi, Biguang Tuo, Taolang Li et Xuemei Liu. « Pathophysiological role of ion channels and transporters in gastrointestinal mucosal diseases ». Cellular and Molecular Life Sciences 78, n^o 24 (15 novembre 2021) : 8109–25. http://dx.doi.org/10.1007/s00018-021-04011-5.

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AbstractThe incidence of gastrointestinal (GI) mucosal diseases, including various types of gastritis, ulcers, inflammatory bowel disease and GI cancer, is increasing. Therefore, it is necessary to identify new therapeutic targets. Ion channels/transporters are located on cell membranes, and tight junctions (TJs) affect acid–base balance, the mucus layer, permeability, the microbiota and mucosal blood flow, which are essential for maintaining GI mucosal integrity. As ion channel/transporter dysfunction results in various GI mucosal diseases, this review focuses on understanding the contribution of ion channels/transporters to protecting the GI mucosal barrier and the relationship between GI mucosal disease and ion channels/transporters, including Cl−/HCO3− exchangers, Cl− channels, aquaporins, Na+/H+ exchangers, and K+ channels. Here, we provide novel prospects for the treatment of GI mucosal diseases.

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Jang, Jun Young, et Se Won Suh. « Structure of STM3169, a tripartite ATP-independent periplasmic transporter ». Acta Crystallographica Section A Foundations and Advances 70, a1 (5 août 2014) : C1653. http://dx.doi.org/10.1107/s2053273314083466.

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Substrate-binding proteins (SBPs) form a group of proteins that are commonly related to membrane protein complexes for transport or cell signal transduction. SBPs are comprised of prokaryotic ATP-binding cassette (ABC)-transporters, prokaryotic tripartite ATP-independent periplasmic (TRAP)-transporters, prokaryotic two-component regulatory systems, eukaryotic guanylatecyclase-atrial natriuretic peptide receptors, G-protein coupled receptors (GPCRs) and ligand-gated ion channels (Berntsson et al., 2010).The TRAP transporters are less known as compared with ABC transporters but are ubiquitous in prokaryotes. The TRAP transporters are important elements of solute uptake systems in prokaryotes. These transporters contain two membrane protein components, predicted to have four and twelve transmembrane helices, respectively. In the TRAP transporters of DctP-type, substrate recognition is mediated through a well-conserved and specific arginine/carboxylate interaction in the SBP (Mulligan et al., 2011). Here we have determined the crystal structure of the TRAP transporter from Salmonella entericaserovarTyphimurium. Unexpectedly, this structure shows that various ligands can bind to the TRAP transporters. It provides insights into substrate binding mechanism in the TRAP transporter system.

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Hui, Wu, Yuan Yongliang, Chen Yongde, Lu Guo, Lan Li, Yang Zhonglin, Ji Hui et Hu Qinghua. « Hypouricemic and Nephroprotective Effects of Emodinol in Oxonate-Induced Hyperuricemic Mice are Mediated by Organic Ion Transporters and OIT3 ». Planta Medica 82, n^o 04 (19 novembre 2015) : 289–97. http://dx.doi.org/10.1055/s-0035-1558212.

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AbstractEmodinol, 1β,3β,23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our research group, has been demonstrated to exhibit uricosuric activity by our previous study. The aim of this study was to evaluate the uricosuric and nephroprotective effects of emodinol and explore its possible mechanisms in potassium oxonate-induced hyperuricemic mice with renal dysfunction. Mice were orally administrated 250 mg/kg of potassium oxonate once daily for 7 consecutive days to induce hyperuricemia with renal dysfunction. Emodinol was given at doses of 25, 50, and 100 mg/kg on the same day 1 h after oxonate treatment, and allopurinol (10 mg/kg) was given as a positive control. After 1 week, serum uric acid, serum creatinine, urine uric acid, urine creatinine, blood urea nitrogen, and hepatic xanthine oxidase activity were determined. The mRNA and protein levels of urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, oncoprotein-induced transcript 3, and organic cation/carnitine transporters in the kidney were detected by real-time polymerase chain reaction and Western blot analysis. In addition, urinary and renal Tamm-Horsfall glycoprotein concentrations were examined by ELISA assays. Emodinol significantly reduced serum urate levels, increased urinary urate levels and fractional excretion of uric acid, and inhibited hepatic xanthine oxidase activity in hyperuricemic mice. Moreover, potassium oxonate administration led to dys expressions of renal urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, and oncoprotein-induced transcript 3 as well as alternations of uromodulin concentrations, which could be reversed by emodinol. On the other hand, treatment of emodinol caused upregulated expressions of organic cation/carnitine transporters, resulting in an improvement of renal function characterized by decreased serum creatinine and blood urea nitrogen levels. Emodinol exhibited hypouricemic and nephroprotective actions by inhibiting xanthine oxidase activity and regulating renal ion transporters and oncoprotein-induced transcript 3, which may be a potential therapeutic agent in hyperuricemia and renal dysfunction.

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Hinds, Bruce J. « Engineering small-ion transporter channels ». Science 372, n^o 6541 (29 avril 2021) : 459–60. http://dx.doi.org/10.1126/science.abh2618.

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Cully, Megan. « Ion transporter agonist improves recovery ». Nature Reviews Drug Discovery 17, n^o 9 (17 août 2018) : 621. http://dx.doi.org/10.1038/nrd.2018.145.

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Mandal, Suraj Kumar, et Shankar Prasad Kanaujia. « Structural and thermodynamic insights into a novel Mg²⁺–citrate-binding protein from the ABC transporter superfamily ». Acta Crystallographica Section D Structural Biology 77, n^o 12 (11 novembre 2021) : 1516–34. http://dx.doi.org/10.1107/s2059798321010457.

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More than one third of proteins require metal ions to accomplish their functions, making them obligatory for the growth and survival of microorganisms in varying environmental niches. In prokaryotes, besides their involvement in various cellular and physiological processes, metal ions stimulate the uptake of citrate molecules. Citrate is a source of carbon and energy and is reported to be transported by secondary transporters. In Gram-positive bacteria, citrate molecules are transported in complex with divalent metal ions, whereas in Gram-negative bacteria they are translocated by Na+/citrate symporters. In this study, the presence of a novel divalent-metal-ion-complexed citrate-uptake system that belongs to the primary active ABC transporter superfamily is reported. For uptake, the metal-ion-complexed citrate molecules are sequestered by substrate-binding proteins (SBPs) and transferred to transmembrane domains for their transport. This study reports crystal structures of an Mg2+–citrate-binding protein (MctA) from the Gram-negative thermophilic bacterium Thermus thermophilus HB8 in both apo and holo forms in the resolution range 1.63–2.50 Å. Despite binding various divalent metal ions, MctA possesses the coordination geometry to bind its physiological metal ion, Mg2+. The results also suggest an extended subclassification of cluster D SBPs, which are known to bind and transport divalent-metal-ion-complexed citrate molecules. Comparative assessment of the open and closed conformations of the wild-type and mutant MctA proteins suggests a gating mechanism of ligand entry following an `asymmetric domain movement' of the N-terminal domain for substrate binding.

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Wang, Cai-Ping, Xing Wang, Xian Zhang, Yun-Wei Shi, Lei Liu et Ling-Dong Kong. « Morin Improves Urate Excretion and Kidney Function through Regulation of Renal Organic Ion Transporters in Hyperuricemic Mice ». Journal of Pharmacy & ; Pharmaceutical Sciences 13, n^o 3 (5 octobre 2010) : 411. http://dx.doi.org/10.18433/j3q30h.

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Purpose. Morin (3,5,7,2′,4′-pentahydroxyflavone), a plant-derived ﬂavonoid, has beneficial effects in animals with various diseases including hyperuricemia and renal dysfunction. Since the decreased renal excretion of uric acid is the hallmark of hyperuricemia and renal dysfunction, here we studied the effects of oral morin administration on renal organic ion transporters in oxonate-induced hyperuricemic mice. Methods. The hyperuricemia in mice was induced by potassium oxonate. Uric acid and creatinine concentrations in urine and serum, and fractional excretion of uric acid (FEUA) were performed to evaluate urate handling. Changes in the expression levels of renal organic ion transporters were detected by Western blotting and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Results. Morin treatment significantly reduced urinary uric acid/creatinine ratio and FEUA, resulting in the reduction of serum uric acid levels in hyperuricemic mice. And kidney dysfunction was also improved after morin treatment in this model. Protein and mRNA levels of renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) were significantly decreased, and renal organic anion transporter (mOAT1) levels were remarkably increased in morin-treated hyperuricemic mice. Morin treatment also blocked down-regulation of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in hyperuricemic mice. Conclusion. These results suggest that morin exhibits uricosuric effect via suppressing urate reabsorption and promoting urate secretion in the kidney of hyperuricemic mice and may help to attenuate deleterious effects of hyperuricemia with renal dysfunction.

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Dashper, S. G., L. Brownfield, N. Slakeski, P. S. Zilm, A. H. Rogers et E. C. Reynolds. « Sodium Ion-Driven Serine/Threonine Transport in Porphyromonas gingivalis ». Journal of Bacteriology 183, n^o 14 (15 juillet 2001) : 4142–48. http://dx.doi.org/10.1128/jb.183.14.4142-4148.2001.

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ABSTRACT Porphyromonas gingivalis is an asaccharolytic, gram-negative bacterium that relies on the fermentation of amino acids for metabolic energy. When grown in continuous culture in complex medium containing 4 mM (each) free serine, threonine, and arginine,P. gingivalis assimilated mainly glutamate/glutamine, serine, threonine, aspartate/asparagine, and leucine in free and/or peptide form. Serine and threonine were assimilated in approximately equal amounts in free and peptide form. We characterized serine transport in this bacterium by measuring uptake of the radiolabeled amino acid in washed cells of P. gingivalis energized with a tetrapeptide not containing serine. Serine was transported by a single system with an affinity constant for transport (Kt ) of 24 μM that was competitively inhibited by threonine. Serine transport was dependent on sodium ion concentration in the suspending buffer, and the addition of the ionophore gramicidin caused the inhibition of serine uptake. Together these data indicate that serine transport was sodium ion-motive force driven. A P. gingivalis gene potentially encoding a serine transporter was identified by sequence similarity to an Escherichia coli serine transporter (SstT). This P. gingivalis gene, designatedsstT, was inactivated by insertion of aBacteroides tetQ gene, producing the mutant W50ST. The mutant was unable to transport serine, confirming the presence of a single serine transporter in this bacterium under these growth conditions. The transport of serine by P. gingivalis was dependent on the presence of free cysteine in the suspension buffer. Other reducing agents were unable to stimulate serine uptake. These data show that P. gingivalisassimilates free serine and threonine from culture media via a cysteine-activated, sodium ion-motive force-driven serine/threonine transporter.

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Jennings, Michael L. « Carriers, exchangers, and cotransporters in the first 100 years of the Journal of General Physiology ». Journal of General Physiology 150, n^o 8 (20 juillet 2018) : 1063–80. http://dx.doi.org/10.1085/jgp.201812078.

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Transporters, pumps, and channels are proteins that catalyze the movement of solutes across membranes. The single-solute carriers, coupled exchangers, and coupled cotransporters that are collectively known as transporters are distinct from conductive ion channels, water channels, and ATP-hydrolyzing pumps. The main conceptual framework for studying transporter mechanisms is the alternating access model, which comprises substrate binding and release events on each side of the permeability barrier and translocation events involving conformational changes between inward-facing and outward-facing conformational states. In 1948, the Journal of General Physiology began to publish work that focused on the erythrocyte glucose transporter—the first transporter to be characterized kinetically—followed by articles on the rates, stoichiometries, asymmetries, voltage dependences, and regulation of coupled exchangers and cotransporters beginning in the 1960s. After the dawn of cDNA cloning and sequencing in the 1980s, heterologous expression systems and site-directed mutagenesis allowed identification of the functional roles of specific amino acid residues. In the past two decades, structures of transport proteins have made it possible to propose specific models for transporter function at the molecular level. Here, we review the contribution of JGP articles to our current understanding of solute transporter mechanisms. Whether the topic has been kinetics, energetics, regulation, mutagenesis, or structure-based modeling, a common feature of these articles has been a quantitative, mechanistic approach, leading to lasting insights into the functions of transporters.

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Deigweiher, Katrin, Nils Koschnick, Hans-Otto Pörtner et Magnus Lucassen. « Acclimation of ion regulatory capacities in gills of marine fish under environmental hypercapnia ». American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 295, n^o 5 (novembre 2008) : R1660—R1670. http://dx.doi.org/10.1152/ajpregu.90403.2008.

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The preservation of ion balance and pH despite environmental fluctuations is essential for the maintenance of vital cellular functions. While several ion transporters contribute to acid-base regulation in fish, the involvement and expression of key transporters under hypercapnia remain to be established. Here, two members of the HCO3− transporter family (Na+/HCO3− cotransporter NBC1 and Cl−/HCO3− exchanger AE1) were described for the first time in gills of marine fish. Benthic eelpout Zoarces viviparus were acclimated to 10,000 ppm CO2. Hypercapnia did not affect whole animal oxygen consumption over a period of 4 days. During a time series of 6 wk NBC1 mRNA levels first decreased by about 40% (8 to 24 h) but finally increased about threefold over control. mRNA expression of AE1 decreased transiently by 50% at day 4 but recovered to control levels only. Reduced mRNA levels were also found for two Na+/H+ exchangers (NHE1A, NHE1B) during the first days (by 50–60% at days 1 and 2), followed by restoration of control levels. This pattern was mirrored in a slight decrease of NHE1 protein contents and its subsequent recovery. In contrast, Na+-K+-ATPase mRNA and protein contents, as well as maximum activity, rose steadily from the onset of hypercapnia, and reached up to twofold control levels at the end. These results indicate shifting acclimation patterns between short- and long-term CO2 exposures. Overall, ion gradient-dependent transporter mRNA levels were transiently downregulated in the beginning of the disturbance. Upregulation of NBC1 on long timescales stresses the importance of this transporter in the hypercapnia response of marine teleosts. Long-term rearrangements include Na+-K+-ATPase at higher densities and capacities, indicating a shift to elevated rates of ion and acid-base regulation under environmental hypercapnia.

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Burtscher, Schicker, Freissmuth et Sandtner. « Kinetic Models of Secondary Active Transporters ». International Journal of Molecular Sciences 20, n^o 21 (28 octobre 2019) : 5365. http://dx.doi.org/10.3390/ijms20215365.

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Kinetic models have been employed to understand the logic of substrate transport through transporters of the Solute Carrier (SLC) family. All SLC transporters operate according to the alternate access model, which posits that substrate transport occurs in a closed loop of partial reactions (i.e., a transport cycle). Kinetic models can help to find realistic estimates for conformational transitions between individual states of the transport cycle. When constrained by experimental results, kinetic models can faithfully describe the function of a candidate transporter at a pre-steady state. In addition, we show that kinetic models can accurately predict the intra- and extracellular substrate concentrations maintained by the transporter at a steady state, even under the premise of loose coupling between the electrochemical gradient of the driving ion and of the substrate. We define the criteria for the design of a credible kinetic model of the SLC transporter. Parsimony is the guiding principle of kinetic modeling. We argue, however, that the level of acceptable parsimony is limited by the need to account for the substrate gradient established by a secondary active transporter, and for random order binding of co-substrates and substrate. Random order binding has consistently been observed in transporters of the SLC group.

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Pifl, C., H. H. Sitte, H. Reither et E. A. Singer. « The mechanism of the releasing action of amphetamine. Uptake, superfusion, and electrophysiological studies on transporter-transfected cells ». Pure and Applied Chemistry 72, n^o 6 (1 janvier 2000) : 1045–50. http://dx.doi.org/10.1351/pac200072061045.

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Amphetamine analogues are able to induce signs of neurotoxicity in the brain. In order to understand this type of neurotoxicity, the interaction of amphetamine with its molecular targets must be elucidated. These molecular targets are plasmalemmal and vesicular monoamine transporters. We investigated the interaction of amphetamine with these transporters in cells transfected with the respective cDNA. Superfusion and whole-cell, patch-clamp experiments were performed, and the toxicity of substrates of the transporters was studied. Amphetamine was taken up by dopamine transporter-expressing cells in a sodium-dependent and cocaine-blockable manner. Furthermore, it elicited inward currents in these cells concentration-dependently. Correlation of uptake, release, and patch-clamp experiments suggest that ion fluxes induced by substrate-gating on transporters may significantly contribute to the releasing action of amphetamine and of other transporter substrates. Dopamine accumulation into serotoninergic terminals depleted of serotonin by 3,4-methylenedioxymethamphetamine was discussed as a mechanism of Ecstasy-toxicity. This is in agreement with a toxic effect of intracellular dopamine which could be demonstrated on our transporter-overexpressing cells. These results, apart from their relevance for the toxicity by amphetamine analogues, may also have bearings on the mechanisms in neurodegenerative diseases affecting monoamine transmitters.

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Kotlyarov, Stanislav, et Anna Kotlyarova. « Analysis of ABC Transporter Gene Expression in Atherosclerosis ». Cardiogenetics 11, n^o 4 (4 novembre 2021) : 204–20. http://dx.doi.org/10.3390/cardiogenetics11040021.

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ABC transporters are a large family of membrane proteins that transport chemically diverse substrates across the cell membrane. Disruption of transport mechanisms mediated by ABC transporters causes the development of various diseases, including atherosclerosis. Methods: A bioinformatic analysis of a dataset from Gene Expression Omnibus (GEO) was performed. A GEO dataset containing data on gene expression levels in samples of atherosclerotic lesions and control arteries without atherosclerotic lesions from carotid, femoral, and infrapopliteal arteries was used for analysis. To evaluate differentially expressed genes, a bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2) and the GEO2R and Phantasus tools (v. 1.11.0). Results: The obtained data indicate the differential expression of many ABC transporters belonging to different subfamilies. The differential expressions of ABC transporter genes involved in lipid transport, mechanisms of multidrug resistance, and mechanisms of ion exchange are shown. Differences in the expression of transporters in tissue samples from different arteries are established. Conclusions: The expression of ABC transporter genes demonstrates differences in atherosclerotic samples and normal arteries, which may indicate the involvement of transporters in the pathogenesis of atherosclerosis.

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Marx, Morgana Tais Streck, Carine de Freitas Souza, Ana Paula Gottlieb Almeida, Sharine Nunes Descovi, Adriane Erbice Bianchini, Juan Antonio Martos-Sitcha, Gonzalo Martínez-Rodríguez, Alfredo Quites Antoniazzi et Bernardo Baldisserotto. « Expression of Ion Transporters and Na+/K+-ATPase and H+-ATPase Activities in the Gills and Kidney of Silver Catfish (Rhamdia quelen) Exposed to Different pHs ». Fishes 7, n^o 5 (27 septembre 2022) : 261. http://dx.doi.org/10.3390/fishes7050261.

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Exposure to acidic and alkaline pHs results in an ionic imbalance. Cellular responses involved in osmoregulation in silver catfish exposed to different pHs (5.5, 7.5, and 9.0) for 24 h were evaluated. The gills and kidney were collected to measure Na+/K+-ATPase (NKA) and H+-ATPase (V-ATPase) activities and to evaluate the expression of ion transporter-related genes: NKA (atp1a1), H+-ATPases (atp6v0a1b, atp6v0a2a, atp6v0a2b), Na+/H+ antiporter (slc9a3), K+/Cl− symporters (slc12a4, slc12a6, slc12a7a, slc12a7b), Na+/K+/2Cl− symporter (slc12a2), and ammonium transporter Rh type b (rhbg). The gills presented greater responses to pH changes than the kidney. The pH alterations changed the atp1a1 gene expression and NKA activity, whereas the H+-ATPase activity increased in the gills in alkaline water, probably to maintain ionic balance. The slc9a3 and slc12a2 genes play more prominent roles in the ion uptake at acidic pH than H+-ATPase. The slc12a7a was the only isoform of this transporter affected by pH. The rhbg is apparently related to ammonia excretion through the gills and kidney (minor scale). Exposure to alkaline pH seems to be battled by impairment of NKA and H+-ATPase activities in the gills, whereas the expression of some ion transporters in silver catfish changes during both acidic and alkaline pHs.

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Cater, Rosemary J., Robert J. Vandenberg et Renae M. Ryan. « Tuning the ion selectivity of glutamate transporter–associated uncoupled conductances ». Journal of General Physiology 148, n^o 1 (13 juin 2016) : 13–24. http://dx.doi.org/10.1085/jgp.201511556.

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The concentration of glutamate within a glutamatergic synapse is tightly regulated by excitatory amino acid transporters (EAATs). In addition to their primary role in clearing extracellular glutamate, the EAATs also possess a thermodynamically uncoupled Cl− conductance. This conductance is activated by the binding of substrate and Na+, but the direction of Cl− flux is independent of the rate or direction of substrate transport; thus, the two processes are thermodynamically uncoupled. A recent molecular dynamics study of the archaeal EAAT homologue GltPh (an aspartate transporter from Pyrococcus horikoshii) identified an aqueous pore at the interface of the transport and trimerization domains, through which anions could permeate, and it was suggested that an arginine residue at the most restricted part of this pathway might play a role in determining anion selectivity. In this study, we mutate this arginine to a histidine in the human glutamate transporter EAAT1 and investigate the role of the protonation state of this residue on anion selectivity and transporter function. Our results demonstrate that a positive charge at this position is crucial for determining anion versus cation selectivity of the uncoupled conductance of EAAT1. In addition, because the nature of this residue influences the turnover rate of EAAT1, we reveal an intrinsic link between the elevator movement of the transport domain and the Cl− channel.

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Yuan, Dumin, Zhiyuan Ma, Biguang Tuo, Taolang Li et Xuemei Liu. « Physiological Significance of Ion Transporters and Channels in the Stomach and Pathophysiological Relevance in Gastric Cancer ». Evidence-Based Complementary and Alternative Medicine 2020 (13 février 2020) : 1–10. http://dx.doi.org/10.1155/2020/2869138.

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Gastric cancer (GC) is a highly invasive and fatal malignant disease that accounts for 5.7% of new global cancer cases and is the third leading cause of cancer-related death. Acid/base homeostasis is critical for organisms because protein and enzyme function, cellular structure, and plasma membrane permeability change with pH. Various ion transporters are expressed in normal gastric mucosal epithelial cells and regulate gastric acid secretion, ion transport, and fluid absorption, thereby stabilizing the differentiation and homeostasis of gastric mucosal epithelial cells. Ion transporter dysfunction results in disordered ion transport, mucosa barrier dysfunction, and acid/base disturbances, causing gastric acid-related diseases such as chronic atrophic gastritis (CAG) and GC. This review summarizes the physiological functions of multiple ion transporters and channels in the stomach, including Cl− channels, Cl−/HCO3− exchangers, sodium/hydrogen exchangers (NHEs), and potassium (K+) channels, and their pathophysiological relevance in GC.

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Bartoszewski, Rafal, Sadis Matalon et James F. Collawn. « Ion channels of the lung and their role in disease pathogenesis ». American Journal of Physiology-Lung Cellular and Molecular Physiology 313, n^o 5 (1 novembre 2017) : L859—L872. http://dx.doi.org/10.1152/ajplung.00285.2017.

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Maintenance of normal epithelial ion and water transport in the lungs includes providing a thin layer of surface liquid that coats the conducting airways. This airway surface liquid is critical for normal lung function in a number of ways but, perhaps most importantly, is required for normal mucociliary clearance and bacterial removal. Preservation of the appropriate level of hydration, pH, and viscosity for the airway surface liquid requires the proper regulation and function of a battery of different types of ion channels and transporters. Here we discuss how alterations in ion channel/transporter function often lead to lung pathologies.

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Motohashi, Hideyuki, Yuji Sakurai, Hideyuki Saito, Satohiro Masuda, Yumiko Urakami, Maki Goto, Atsushi Fukatsu, Osamu Ogawa et Ken-ichi Inui. « Gene Expression Levels and Immunolocalization of Organic Ion Transporters in the Human Kidney ». Journal of the American Society of Nephrology 13, n^o 4 (avril 2002) : 866–74. http://dx.doi.org/10.1681/asn.v134866.

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ABSTRACT. Renal excretion of organic anions and cations is mediated by the organic ion transporter family (SLC22A). In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney. The expression level of hOAT3 mRNA was the highest among the organic ion transporter family, followed by that of hOAT1 mRNA. The hOCT2 mRNA level was the highest in the human OCT family, and the level of hOCTN2 mRNA was higher than that of hOCTN1. hOCT1 mRNA showed the lowest level of expression in organic ion transporter family. hOAT1, hOAT3, and hOCT2 proteins were detected in crude membranes from the kidney of all patients by Western blot analyses, whereas hOCT1 protein could not be detected. Immunohistochemical analyses showed that both hOAT1 and hOAT3 were localized to the basolateral membrane of the proximal tubules in the cortex, and hOCT2 was localized to the basolateral membrane of the proximal tubules in both the cortex and medullary ray. Immunohistochemical analyses of serial sections indicated that hOAT1, hOAT3, and hOCT2 were coexpressed in a portion of the proximal tubules. These results suggest that hOAT1, hOAT3, and hOCT2 play predominant roles in the transport of organic ions across the basolateral membrane of human proximal tubules.

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Rudnick, Gary, et Walter Sandtner. « Serotonin transport in the 21st century ». Journal of General Physiology 151, n^o 11 (30 septembre 2019) : 1248–64. http://dx.doi.org/10.1085/jgp.201812066.

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Serotonin (5-hydroxytryptamine [5-HT]) is accumulated within nerve endings by the serotonin transporter (SERT), which terminates its extracellular action and provides cytoplasmic 5-HT for refilling of synaptic vesicles. SERT is the target for many antidepressant medications as well as psychostimulants such as cocaine and ecstasy (3,4-methylenedioxymethamphetamine). SERT belongs to the SLC6 family of ion-coupled transporters and is structurally related to several other transporter families. SERT was studied in the 1970s and 1980s using membrane vesicles isolated from blood platelets. These studies led to a proposed stoichiometry of transport that has been challenged by high-resolution structures of SERT and its homologues and by studies of SERT electrophysiology. Here, we review the original evidence alongside more recent structural and electrophysiological evidence. A self-consistent picture emerges with surprising insights into the ion fluxes that accompany 5-HT transport.

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Dubyak, George R. « Ion homeostasis, channels, and transporters : an update on cellular mechanisms ». Advances in Physiology Education 28, n^o 4 (décembre 2004) : 143–54. http://dx.doi.org/10.1152/advan.00046.2004.

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The steady-state maintenance of highly asymmetric concentrations of the major inorganic cations and anions is a major function of both plasma membranes and the membranes of intracellular organelles. Homeostatic regulation of these ionic gradients is critical for most functions. Due to their charge, the movements of ions across biological membranes necessarily involves facilitation by intrinsic membrane transport proteins. The functional characterization and categorization of membrane transport proteins was a major focus of cell physiological research from the 1950s through the 1980s. On the basis of these functional analyses, ion transport proteins were broadly divided into two classes: channels and carrier-type transporters (which include exchangers, cotransporters, and ATP-driven ion pumps). Beginning in the mid-1980s, these functional analyses of ion transport and homeostasis were complemented by the cloning of genes encoding many ion channels and transporter proteins. Comparison of the predicted primary amino acid sequences and structures of functionally similar ion transport proteins facilitated their grouping within families and superfamilies of structurally related membrane proteins. Postgenomics research in ion transport biology increasingly involves two powerful approaches. One involves elucidation of the molecular structures, at the atomic level in some cases, of model ion transport proteins. The second uses the tools of cell biology to explore the cell-specific function or subcellular localization of ion transport proteins. This review will describe how these approaches have provided new, and sometimes surprising, insights regarding four major questions in current ion transporter research. 1) What are the fundamental differences between ion channels and ion transporters? 2) How does the interaction of an ion transport protein with so-called adapter proteins affect its subcellular localization or regulation by various intracellular signal transduction pathways? 3) How does the specific lipid composition of the local membrane microenvironment modulate the function of an ion transport protein? 4) How can the basic functional properties of a ubiquitously expressed ion transport protein vary depending on the cell type in which it is expressed?

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Powell, J. J., R. Jugdaohsingh et R. P. H. Thompson. « The regulation of mineral absorption in the gastrointestinal tract ». Proceedings of the Nutrition Society 58, n^o 1 (février 1999) : 147–53. http://dx.doi.org/10.1079/pns19990020.

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The absorption of metal ions in the mammalian single-stomached gut is fortunately highly selective, and both luminal and tissue regulation occur. Initially, assimilation of metal ions in an available form is facilitated by the intestinal secretions, chiefly soluble mucus (mucin) that retards hydrolysis of ions such as Cu, Fe and Zn. Metal ions then bind and traverse the mucosally-adherent mucus layer with an efficiency M+> M2+> M3+. At the mucosa Fe3+is probably uniquely reduced to Fe2+, and all divalent cations (including Fe2+) are transported by a membrane protein (such as divalent cation transporter 1) into the cell. This minimizes absorption of toxic trivalent metals (e.g. A13+). Intracellular metal-binding molecules (such as mobilferrin) may be present at the intracellular side of the apical membrane, anchored to a transmembrane protein such as an integrin complex. This mobilferrin would receive the metal ion from divalent cation transporter 1 and, with part of the integrin molecule, transport the metal to the cytosol for safe sequestration in a larger complex such as ferritin or‘paraferritin’. β2-Microglobulin and HFE (previously termed human leucocyte antigen H) may be involved in stabilizing metal mobilferrin-integrin to form this latter complex. Finally, a systemic metal-binding protein such as transferrin may enter the antiluminal (basolateral) side of the cell for binding of the sequestered metal ion and delivery to the circulation. Regulatory proteins, such as HFE, may determine the degree of ion transport from intestinal cells to the circulation. Gradients in pH and perhaps pCa or even pNa could allow the switching of ions between the different transporters throughout this mechanism.

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PRICHARD, R. K., et A. ROULET. « ABC transporters and β-tubulin in macrocyclic lactone resistance : prospects for marker development ». Parasitology 134, n^o 8 (3 juillet 2007) : 1123–32. http://dx.doi.org/10.1017/s0031182007000091.

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SUMMARYMacrocyclic lactones (MLs) are highly lipophilic anthelmintics which are known to bind to and open ligand-gated ion channels. However, these anthelmintics, and particularly the avermectin members of the ML class of endectocides, are potent substrates for ABC transporters and these transporters may regulate drug concentration in both the host and the parasite. There is accumulating evidence that ivermectin (IVM), and to a lesser extent moxidectin (MOX), selects for certain alleles of P-glycoprotein and other ABC transporter genes, selects for constitutive overexpression of some of these gene products, and induces overexpression of some P-glycoproteins in nematodes. However, such mechanisms of ML resistance do not easily lend themselves to the identification of SNP markers for resistance because of the diversity of ABC transporters in nematodes, the apparent diversity of effects of different MLs, and because regulatory elements for ABC transporter gene expression are not well understood in nematodes. Another non ligand-gated ion channel gene which appears to be under IVM selection, at least in Onchocerca volvulus and Haemonchus contortus, is β-tubulin, and a simple genetic test for this selection has been described in O. volvulus. However, further work is required to elucidate a reliable marker associated with this gene in H. contortus or other parasitic nematodes of livestock. The possible involvement of ABC transporter genes and β-tubulin in ML resistance provides a start in developing our understanding of this phenotype and markers for its detection in field populations of parasitic nematodes. However, more work is required before these leads can provide practical SNP markers for ML resistance.

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SCHWIEBERT, ERIK M., DALE J. BENOS, MARIE E. EGAN, M. JACKSON STUTTS et WILLIAM B. GUGGINO. « CFTR Is a Conductance Regulator as well as a Chloride Channel ». Physiological Reviews 79, n^o 1 (1 janvier 1999) : S145—S166. http://dx.doi.org/10.1152/physrev.1999.79.1.s145.

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Schwiebert, Erik M., Dale J. Benos, Marie E. Egan, M. Jackson Stutts, and William B. Guggino. CFTR Is a Conductance Regulator as well as a Chloride Channel. Physiol. Rev. 79, Suppl.: S145–S166, 1999. — Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter gene family. Although CFTR has the structure of a transporter that transports substrates across the membrane in a nonconductive manner, CFTR also has the intrinsic ability to conduct Cl− at much higher rates, a function unique to CFTR among this family of ABC transporters. Because Cl− transport was shown to be lost in cystic fibrosis (CF) epithelia long before the cloning of the CF gene and CFTR, CFTR Cl− channel function was considered to be paramount. Another equally valid perspective of CFTR, however, derives from its membership in a family of transporters that transports a multitude of different substances from chemotherapeutic drugs, to amino acids, to glutathione conjugates, to small peptides in a nonconductive manner. Moreover, at least two members of this ABC transporter family ( mdr-1, SUR) can regulate other ion channels in the membrane. More simply, ABC transporters can regulate somehow the function of other cellular proteins or cellular functions. This review focuses on a plethora of studies showing that CFTR also regulates other ion channel proteins. It is the hope of the authors that the reader will take with him or her the message that CFTR is a conductance regulator as well as a Cl− channel.

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Zhou, Ming. « Ion Selectivity and Permeation in a Potassium Ion Transporter ». Biophysical Journal 100, n^o 3 (février 2011) : 6a. http://dx.doi.org/10.1016/j.bpj.2010.12.245.

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Galli, A., L. J. DeFelice, B. J. Duke, K. R. Moore et R. D. Blakely. « Sodium-dependent norepinephrine-induced currents in norepinephrine-transporter-transfected HEK-293 cells blocked by cocaine and antidepressants. » Journal of Experimental Biology 198, n^o 10 (1 octobre 1995) : 2197–212. http://dx.doi.org/10.1242/jeb.198.10.2197.

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Transport of norepinephrine (NE+) by cocaine- and antidepressant-sensitive transporters in presynaptic terminals is predicted to involve the cotransport of Na+ and Cl-, resulting in a net movement of charge per transport cycle. To explore the relationship between catecholamine transport and ion permeation through the NE transporter, we established a human norepinephrine transporter (hNET) cell line suitable for biochemical analysis and patch-clamp recording. Stable transfection of hNET cDNA into HEK-293 (human embryonic kidney) cells results in lines exhibiting (1) a high number of transporter copies per cell (10(6)), as detected by radioligand binding and hNET-specific antibodies, (2) high-affinity, Na(+)-dependent transport of NE, and (3) inhibitor sensitivities similar to those of native membranes. Whole-cell voltage-clamp of hNET-293 cells reveals NE-induced, Na(+)-dependent currents blocked by antidepressants and cocaine that are absent in parental cells. In addition to NE-dependent currents, transfected cells posses an NE-independent mode of charge movement mediated by hNET. hNET antagonists without effect in non-transfected cells abolish both NE-dependent and NE-independent modes of charge movement in transfected cells. The magnitude of NE-dependent currents in these cells exceeds the expectations of simple carrier models using previous estimates of transport rates. To explain our observations, we propose that hNETs function as ion-gated ligand channels with an indefinite stoichiometry relating ion flux to NE transport. In this view, external Na+ and NE bind to the transporter with finite affinities in a cooperative fashion. However, coupled transport may not predict the magnitude or the kinetics of the total current through the transporter. We propose instead that Na+ gates NE transport and also the parallel inward flux of an indeterminate number of ions through a channel-like pore.

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Haase, J., A. M. Killian, F. Magnani et C. Williams. « Regulation of the serotonin transporter by interacting proteins ». Biochemical Society Transactions 29, n^o 6 (1 novembre 2001) : 722–28. http://dx.doi.org/10.1042/bst0290722.

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The serotonin transporter (SERT) plays a critical role in the maintenance of normal neurotransmission by serotonin [5-hydroxytryptamine (5-HT)]. Recent evidence suggests that SERT and other neurotransmitter transporters are tightly regulated. Activation of protein kinase C results in a decrease in SERT-mediated 5-HT uptake, which is due to an internalization of the transporter. However, to date little is known about the mechanism and proteins involved in the down-regulation of the transporter. One candidate SERT-regulatory protein is the SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) protein, syntaxin 1A (Syn1A), which has recently been implicated in the regulation of ion channels as well as the SERT-related γ-aminobutyric acid- and glycine-transporters. Using 5-HT uptake assays, confocal microscopy and glutathione S-transferase (GST) pull-down assays we showed that Syn1A also interacts with SERT and alters the subcellular localization of the transporter, resulting in a reduction of 5-HT transport. In addition, we have used the yeast two-hybrid system to search for novel regulatory proteins that interact with the cytoplasmic N-terminal domain of SERT. By screening rat brain cDNA library we have identified six potential SERT-binding proteins. Here we also present progress towards the elucidation of the biological relevance of these proteins and their potential role for the regulation of the serotonin transporter.

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Kowalczyk, Amanda, Omotola Gbadamosi, Kathryn Kolor, Jahree Sosa, Livia Andrzejczuk, Gregory Gibson, Claudette St Croix et al. « Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter ». Biochemical Journal 478, n^o 17 (7 septembre 2021) : 3205–20. http://dx.doi.org/10.1042/bcj20210342.

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Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.

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Ishitani, Ryuichiro, Yuji Sugita, Naoshi Dohmae, Noritaka Furuya, Motoyuki Hattori et Osamu Nureki. « Mg2+-sensing mechanism of Mg2+ transporter MgtE probed by molecular dynamics study ». Proceedings of the National Academy of Sciences 105, n^o 40 (1 octobre 2008) : 15393–98. http://dx.doi.org/10.1073/pnas.0802991105.

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Proper regulation of the intracellular ion concentration is essential to maintain life and is achieved by ion transporters that transport their substrates across the membrane in a strictly regulated manner. MgtE is a Mg2+ transporter that may function in the homeostasis of the intracellular Mg2+ concentration. A recent crystallographic study revealed that its cytosolic domain undergoes a Mg2+-dependent structural change, which is proposed to gate the ion-conducting pore passing through the transmembrane domain. However, the dynamics of Mg2+ sensing, i.e., how MgtE responds to the change in the intracellular Mg2+ concentration, remained elusive. Here we performed molecular dynamics simulations of the MgtE cytosolic domain. The simulations successfully reproduced the structural changes of the cytosolic domain upon binding or releasing Mg2+, as well as the ion selectivity. These results suggested the roles of the N and CBS domains in the cytosolic domain and their respective Mg2+ binding sites. Combined with the current crystal structures, we propose an atomically detailed model of Mg2+ sensing by MgtE.

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Schwartz, E. A. « Transport-Mediated Synapses in the Retina ». Physiological Reviews 82, n^o 4 (10 janvier 2002) : 875–91. http://dx.doi.org/10.1152/physrev.00010.2002.

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Most synapses rely on regulated exocytosis for determining the concentration of transmitter in the synaptic cleft. However, this mechanism may not be universal. Several synapses in the retina appear to use a synaptic machinery in which transmitter transporters play an essential role. Two types of transport-mediated synapses have been proposed. These synapses have been best observed in horizontal cells and cones of nonmammalian retinas. Horizontal cells use a transporter to mediate a bidirectional shuttle, whose balance point is set by ion concentrations and voltage. Nonmammalian cones combine exocytosis and the activity of a transporter. Because exocytosis is voltage independent over most of a cone's physiological voltage range, a voltage-dependent transporter determines the concentration of transmitter in the synaptic cleft. These two synapses may be models for transport-mediated synapses that operate in other parts of the brain.

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Liang, Hong, Christopher H. Ko, Todd Herman et Richard F. Gaber. « Trinucleotide Insertions, Deletions, and Point Mutations in Glucose Transporters Confer K+ Uptake inSaccharomyces cerevisiae ». Molecular and Cellular Biology 18, n^o 2 (1 février 1998) : 926–35. http://dx.doi.org/10.1128/mcb.18.2.926.

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ABSTRACT Deletion of TRK1 and TRK2 abolishes high-affinity K+ uptake in Saccharomyces cerevisiae, resulting in the inability to grow on typical synthetic growth medium unless it is supplemented with very high concentrations of potassium. Selection for spontaneous suppressors that restored growth of trk1Δ trk2Δ cells on K+-limiting medium led to the isolation of cells with unusual gain-of-function mutations in the glucose transporter genesHXT1 and HXT3 and the glucose/galactose transporter gene GAL2. 86Rb uptake assays demonstrated that the suppressor mutations conferred increased uptake of the ion. In addition to K+, the mutant hexose transporters also conferred permeation of other cations, including Na+. Because the selection strategy required such gain of function, mutations that disrupted transporter maturation or localization to the plasma membrane were avoided. Thus, the importance of specific sites in glucose transport could be independently assessed by testing for the ability of the mutant transporter to restore glucose-dependent growth to cells containing null alleles of all of the known functional glucose transporter genes. Twelve sites, most of which are conserved among eukaryotic hexose transporters, were revealed to be essential for glucose transport. Four of these have previously been shown to be essential for glucose transport by animal or plant transporters. Eight represented sites not previously known to be crucial for glucose uptake. Each suppressor mutant harbored a single mutation that altered an amino acid(s) within or immediately adjacent to a putative transmembrane domain of the transporter. Seven of 38 independent suppressor mutations consisted of in-frame insertions or deletions. The nature of the insertions and deletions revealed a striking DNA template dependency: each insertion generated a trinucleotide repeat, and each deletion involved the removal of a repeated nucleotide sequence.

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Foot, Natalie J., Hazel E. Dalton, Linda M. Shearwin-Whyatt, Loretta Dorstyn, Seong-Seng Tan, Baoli Yang et Sharad Kumar. « Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2 ». Blood 112, n^o 10 (15 novembre 2008) : 4268–75. http://dx.doi.org/10.1182/blood-2008-04-150953.

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AbstractMany ion channels and transporters are regulated by ubiquitination mediated by the Nedd4 family of HECT-type ubiquitin ligases (E3s). These E3s commonly interact with substrates via their WW domains that bind to specific motifs in target proteins. However, not all potential targets of these E3s contain WW-binding motifs. Therefore, accessory proteins may mediate the interaction between Nedd4 family members and their targets. Here we report that the divalent metal ion transporter DMT1, the primary nonheme iron transporter in mammals, is regulated by ubiquitination mediated by the Nedd4 family member WWP2. DMT1 interacts with 2 WW domain-interacting proteins, Ndfip1 and Ndfip2, previously proposed to have roles in protein trafficking. This promotes DMT1 ubiquitination and degradation by WWP2. Consistent with these observations, Ndfip1−/− mice show increased DMT1 activity and a concomitant increase in hepatic iron deposition, indicating an essential function of Ndfip1 in iron homeostasis. This novel mechanism of regulating iron homeostasis suggests that Ndfips and WWP2 may contribute to diseases involving aberrant iron transport.

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Bai, Yonghong, Min Li et Tzyh-Chang Hwang. « Structural basis for the channel function of a degraded ABC transporter, CFTR (ABCC7) ». Journal of General Physiology 138, n^o 5 (31 octobre 2011) : 495–507. http://dx.doi.org/10.1085/jgp.201110705.

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Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily, but little is known about how this ion channel that harbors an uninterrupted ion permeation pathway evolves from a transporter that works by alternately exposing its substrate conduit to the two sides of the membrane. Here, we assessed reactivity of intracellularly applied thiol-specific probes with cysteine residues substituted into the 12th transmembrane segment (TM12) of CFTR. Our experimental data showing high reaction rates of substituted cysteines toward the probes, strong blocker protection of cysteines against reaction, and reaction-induced alterations in channel conductance support the idea that TM12 of CFTR contributes to the lining of the ion permeation pathway. Together with previous work, these findings raise the possibility that pore-lining elements of CFTR involve structural components resembling those that form the substrate translocation pathway of ABC transporters. In addition, comparison of reaction rates in the open and closed states of the CFTR channel leads us to propose that upon channel opening, the wide cytoplasmic vestibule tightens and the pore-lining TM12 rotates along its helical axis. This simple model for gating conformational changes in the inner pore domain of CFTR argues that the gating transition of CFTR and the transport cycle of ABC proteins share analogous conformational changes. Collectively, our data corroborate the popular hypothesis that degradation of the cytoplasmic-side gate turned an ABC transporter into the CFTR channel.

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