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PubMed1991

Adenosine transport and nitrobenzylthioinosine binding in human placental membrane vesicles from brush-border and basal sides of the trophoblast.

The nucleoside transport activity of human placental syncytiotrophoblast brush-border and basal membrane vesicles was compared. Adenosine and uridine were taken up into an osmotically active space. Adenosine was rapidly metabolized to inosine, metabolism was blocked by preincubating vesicles with 2'-deoxycoformycin, and subsequent adenosine uptake studies were performed in the presence of 2'-deoxycoformycin. Adenosine influx by brush-border membrane vesicles was fitted to a two-component system consisting of a saturable system with apparent Michaelis-Menten kinetics (apparent Km approx. 150 microM) and a linear component. Adenosine uptake by the saturable system was blocked by nitrobenzylthioinosine (NBMPR), dilazep, dipyridamole and other nucleosides. Inhibition by NBMPR was associated with high-affinity binding of NBMPR to the brush-border membrane vesicles (apparent Kd 0.98 +/- 0.21 nM). Binding of NBMPR to these sites was blocked by adenosine, inosine, uridine, thymidine, dilazep and dipyridamole, and the respective apparent Ki values were 0.23 +/- 0.012, 0.36 +/- 0.035, 0.78 +/- 0.1, 0.70 +/- 0.12 (mM), and 0.12 and 4.2 +/- 1.4 (nM). In contrast, adenosine influx by basal membrane vesicles was low (less than 10% of the rate observed with brush-border membrane vesicles under similar conditions), and hence no quantitative studies of adenosine uptake could be performed with these vesicles. Nevertheless, high-affinity NBMPR binding sites were demonstrated in basal membrane vesicles with similar properties to those in brush-border membrane vesicles (apparent Kd 1.05 +/- 0.13 nM and apparent Ki values for adenosine, inosine, uridine, thymidine, dilazep and dipyridamole of 0.14 +/- 0.045, 0.54 +/- 0.046, 1.26 +/- 0.20, 1.09 +/- 0.18 mM and 0.14 and 3.7 +/- 0.5 nM, respectively). Exposure of both membrane vesicles to UV light in the presence of [3H]NBMPR resulted in covalent labeling of a membrane protein(s) with a broad apparent Mr on SDS gel electropherograms of 77,000-45,000, similar to that previously reported for many other tissues, including human erythrocytes. We conclude that the maternal (brush-border) and fetal (basal) surfaces of the human placental syncytiotrophoblast possess broad-specificity, facilitated-diffusion, NBMPR-sensitive nucleoside transporters.

Adenosine↗
PubMed1981

Dopamine uptake in platelets: two different low-affinity, saturable mechanisms.

Uptake of dopamine (DA) in human blood platelets was found to encompass two different saturable components, one chloride-dependent and one non-chloride-dependent. The chloride-dependent uptake had an apparent Km of about 4 X 10(-5) M, was strongly inhibited by serotonin (5HT), and moderately inhibited by ouabain, PHMB and by substituting K+ for Na+ in the incubation medium. The antidepressants imipramine, clomipramine, desipramine and nomifensine showed approximately the same inhibitory potency against this uptake as against 5HT uptake in platelets. This chloride-dependent mechanism is probably identical with the 5HT uptake mechanism in platelets. The non-chloride-dependent uptake had an apparent Km of about 1.4 X 10(-4) M, and was not inhibited by metabolic inhibitors or antidepressants, and only moderately by 5HT. Its characteristics seem to be in accordance with facilitated diffusion. When platelets preloaded with DA were reincubated in fresh medium without chloride, the efflux curve indicated a distribution between one "superficial" and one "deep" compartment, containing 68% and 32% of total platelet DA, respectively. The deep compartment probably corresponds to the dense osmiophilic granules. The efflux kinetics are similar to those found for 5HT.

Antidepressive Agents, Tricyclic↗
PubMed1990

Interaction of mitochondrial porin with cytosolic proteins.

Intracellular phosphorylation is an important step in active uptake and utilization of carbohydrates. For example glucose and glycerol enter the liver cell along the extra intracellular gradient by facilitated diffusion through specific carriers and are concentrated inside the cell by phosphorylation via hexokinase or glycerol kinase. Depending on the function of the respective tissue the uptake of carbohydrates serves different metabolic purposes. In brain and kidney medulla cells which depend on carbohydrates, glucose and glycerol are taken up according to the energy demand. However, in tissues such as muscle which synthesize glycogen or like liver which additionally produce fat from glucose, the uptake of carbohydrates has to be regulated according to the availability of glucose and glycerol. How the reversible coupling of the kinases to the outer membrane pore and the mitochondrial ATP serves to fulfil these specific requirements will be explained as well as how this regulates the carbohydrate uptake in brain according to the activity of the oxidative phosphorylation and how this allows glucose uptake in liver and muscle to persist in the presence of high glucose 6-phosphate without activating the rate of glycolysis.

Cytosol↗
PubMed1994

A mathematical model for the inhibition of the multidrug resistance-associated P-glycoprotein pump.

An extension of an earlier model of the p170 glycoprotein pump is presented. In an earlier work (Michelson and Slate, Bull. math. Biol. 54, 1023-1038, 1992), the pump was modeled using an energy-dependent model of facilitated diffusion. In this paper we add an inhibitor to the model. New equations are derived which represent either competitive or non-competitive inhibition in the pumping action of the glycoprotein. Numerical simulations were run which provide a response surface (initial loading concentration of inhibitor and its ability to compete with an ideal anti-cancer drug vs a summary measure of cytoplasmic exposure) for each scenario. The importance of the exposure profile, how it is related to ultimate tumor cell survival, and the binding requirements for developing multidrug resistance inhibitors are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Linoleic acid absorption in the unanesthetized rat: mechanism of transport and influence of luminal factors on absorption.

Linoleic acid intestinal absorption was studied in the unanesthetized rat. At low (21-1260 micrometer) intraluminal concentrations, absorption took place by facilitated diffusion; while at high (1.26-2.5 mM) concentrations, simple diffusion was the predominant mechanism of transport. At low concentrations (840 micrometer), the equimolar additions of oleic, linolenic, and arachidonic acids or lecithin inhibited the absorption of linoleic acid. Substitution of potassium for sodium in the buffer solution, substitution of Tween 80 for sodium taurocholate, or decrease in the hydrogen ion concentration all resulted in decreased rate of linoleic acid absorption. Increase in sodium taurocholate concentration, or perfusate flow rate increased linoleic acid's absorption. These experiments demonstrate that linoleic acid is absorbed by a concentration-dependent dual mechanism of transport. The absorption rate is modified by the pH, surfactant type and concentration, the simultaneous presence of other polyunsaturated fatty acids, and the thickness of the unstirred water layer.

Animals↗
PubMed1978

Arachidonic acid intestinal absorption: mechanism of transport and influence of luminal factors of absorption in vitro.

The mechanism and characteristics of intestinal absorption of arachidonic acid were studied in vitro using everted intestinal sacs of the rat. Arachidonic acid absorption was studied at concentrations of 5 micron to 8.36 mM. The plot of absorption rate vs. concentration fitted best to a rectangular hyperbola at low micron concentrations and to a straight linear relationship in the mM range of concentrations. Metabolic inhibitors and uncouplers did not change absorption in either range of concentrations. The absorption of arachidonic acid increased with thinning of the unstirred water-layer, decrease in the pH, or the substitution of sodium taurocholate by Pluronic F 68 OR Tween 80. Absorption decreased following the equimolar additions of oleic, linoleic, and linolenic acids. Absorption rate did not change when the taurocholate concentration was varied from 5-15 mM or following the additions of butyric or glutamic acids, leucine, lysine, or dextrose. It was concluded that arachidonic acid is absorbed by a concentration-dependent dual mechanism of transport which is not energy dependent. At the low micron range of concentrations, facilitated diffusion is predominant, while at mM concentrations, simple diffusion is the dominant mechanism of absorption. Changes in the intestinal fluid composition, flow rate, and pH can modify the rate of absorption of arachidonic acid.

Animals↗
PubMed1982

Maltotriose transport and utilization in baker's and brewer's yeast.

Maltotriose is metabolized by baker's and brewer's yeast only oxidatively, with a respiratory quotient of 1.0, the QCO2Ar being, depending on the strain used, 0-11, as compared with QCO2air of 6-42 microL CO2 per h per mg dry substance. The transport appeared to proceed by facilitated diffusion (no effects of NaF, iodoacetamide and 3-chlorophenylhydrazonomalononitrile) with a KT of more than 50 mM and was inhibited by maltose greater than maltotriose greater than methyl-alpha-D-glucoside greater than maltotetraose greater than D-fructose greater than D-glucose. The transport was present constitutively in both Saccharomyces cerevisiae (baker's yeast) and in S. uvarum (brewer's yeast) and it was not significantly stimulated by preincubation with glucose or maltose. The pH optimum was 4.5-5.5, the temperature dependence yielded an activation energy of 26 kJ/mol.

Biological Transport↗
PubMed2004

Overview of mammalian zinc transporters.

In recent years, a number of mammalian zinc transporters have been identified, and candidate genes are rapidly growing. These transporters are classified into two families: ZIP (ZRT, IRT-like protein) and CDF (cation diffusion facilitator). ZIP members facilitate zinc influx into the cytosol, while CDF members facilitate its efflux from the cytosol. Molecular characterization of the transporters has brought about major advances in our understanding of their physiological functions. Zinc metabolism is regulated primarily through zinc-dependent control of transcription, translation, and intracellular trafficking of transporters. Analyses of mice whose zinc transporter genes have been genetically disrupted and of the naturally occurring mutant mice with symptoms related to abnormal zinc metabolism have provided compelling evidence that some zinc transporters play critical roles in zinc homeostasis. In this review, we review the literature of mammalian zinc transporters with emphasis on very recent findings and elicit integrative knowledge of zinc homeostasis.

Animals↗
PubMed2004

FieF (YiiP) from Escherichia coli mediates decreased cellular accumulation of iron and relieves iron stress.

The Escherichia coli yiiP gene encodes an iron transporter, ferrous iron efflux (FieF), which belongs to the cation diffusion facilitator family (CDF). Transcription of fieF correlated with iron concentration; however, expression appeared to be independent of the ferrous iron uptake regulator Fur. Absence of FieF led to decreased growth of E. coli cells in complex growth medium but only if fur was additionally deleted. The presence of EDTA was partially able to relieve this growth deficiency. Expression of fieF in trans rendered the double deletion strain more tolerant to iron. Furthermore, E. coli cells exhibited reduced accumulation of (55)Fe when FieF was expressed in trans. FieF catalyzed active efflux of Zn(II) in antiport with protons energized by NADH via the transmembrane pH gradient in everted membrane vesicles. Using the iron-sensitive fluorescent indicator PhenGreen-SK encapsulated in proteoliposomes, transmembrane fluxes of iron cations were measured with purified and reconstituted FieF by fluorescence quenching. This suggests that FieF is an iron and zinc efflux system, which would be the first example of iron detoxification by efflux in any organism.

Bacterial Proteins↗
PubMed2001

2-Oxoglutarate transport system in Staphylococcus aureus.

2-[(14)C]oxoglutarate uptake in resting cells of Staphylococcus aureus 17810S occurs via two kinetically different systems: (1) a secondary, electrogenic 2-oxoglutarate:H(+) symporter (K(m)=0.105 mM), energized by an electrochemical proton potential (Delta mu H(+)) that is generated by the oxidation of endogenous amino acids and sensitive to ionophores, and (2) a Delta mu H(+)-independent facilitated diffusion system (K(m)=1.31 mM). The 2-oxoglutarate transport system of S. aureus 17810S can be classified as a new member of the MHS (metabolite:H(+) symporter) family. This transporter takes up various dicarboxylic acids in the order of affinity: succinate = malate > fumarate > 2-oxoglutarate > glutamate. Energy conservation with 2-oxoglutarate was studied in starved cells of strain 17810S. Initial transport of 2-oxoglutarate in these cells is energized by Delta mu H(+) generated via hydrolysis of residual ATP. Subsequent oxidation of the accumulated 2-oxoglutarate generates Delta mu H(+) for further, autoenergized transport of this 2-oxoacid and also for Delta mu H(+)-linked resynthesis of ATP. In the cadmium-sensitive S. aureus 17810S, Cd(2+) accumulation strongly inhibits energy conservation with 2-oxoglutarate at the level of Delta mu H(+) generation, without direct blocking of the 2-oxoglutarate transport system or ATP synthase complex. In the cadmium-resistant S. aureus 17810R, Cd(2+) does not affect energy conservation due to its extrusion by the Cd(2+) efflux system (Cd(2+)-ATPase of P-type), which prevents Cd(2+) accumulation.

Adenosine Triphosphate↗
PubMed1997

A novel family of ubiquitous heavy metal ion transport proteins.

We describe a novel diverse family of metal ion transporter (CDF) proteins (the cation diffusion facilitator (CDF) family) with members occurring in both prokaryotes and eukaryotes. Thirteen sequenced protein members of the CDF family have been identified, several of which have been shown to transport cobalt, cadmium and/or zinc. All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners, and on the basis of the analyses, we present a unified structural model. Members of the family are shown to exhibit an unusual degree of size variation, sequence divergence, and differences in cell localization and polarity. The phylogenetic tree for the CDF family reveals that prokaryotic and eukaryotic proteins cluster separately. It allows functional predictions for some uncharacterized members of this family. A signature sequence specific for the CDF family is derived.

Amino Acid Sequence↗
PubMed2002

How to get from A to B: strategies for analysing protein motion on DNA.

Essentially all genetic events require proteins to move from one location in a DNA polymer to another location in the same chain. A protein will seldom bind to a specific site in the DNA by colliding directly with that site. Instead, the protein will almost always collide first with a random site anywhere in the DNA and then migrate to the specific site by a facilitated-diffusion process that is constrained to the zone of that DNA molecule. Thereafter, many proteins bound to their target sites translocate in a specified direction along the DNA by a energy-dependent vectorial mechanism. This review will discuss some of the strategies that have been developed to analyse the motion of proteins on DNA, with respect to both the random diffusion processes involved in target-site location by DNA-binding proteins and the vectorial processes involved in unidirectional translocation along DNA.

DNA↗
PubMed1996

Transport mechanism of anthracycline derivatives in human leukemia cell lines: uptake and efflux of pirarubicin in HL60 and pirarubicin-resistant HL60 cells.

We studied the transport mechanism of pirarubicin (THP) in HL60 and its THP-resistant (HL60/THP) cells, which showed no expression of mdr1 mRNA on Northern blot analysis. Under physiological conditions, the uptake of THP by both types of cell was time- and temperature-dependent. The amount of drug transport in the resistant cells was significantly less than that in the parent cells within 3 min of incubation. THP uptake was significantly higher in the presence than in the absence of 4 mM 2,4-dinitrophenol (DNP) in glucose-free Hanks' balanced salt solution in both HL60 and HL60/THP cells and the increases were approximately equal. In the presence of DNP, the uptake of THP by both types of cell was concentration-dependent, and there were no significant differences in the apparent kinetic constants (Michaelis constant (Km), maximum velocity (Vmax) and Vmax/Km) for THP uptake between HL60 and HL60/THP cells. Additionally, THP transport was competitively inhibited by its analogue doxorubicin. The efflux of THP from HL60/THP cells was significantly greater than that from HL60 cells, and the release from both types of cell was completely inhibited by decreasing the incubation temperature to 0 degrees C and by treatment with DNP in glucose-free medium. In contrast, the P-glycoprotein inhibitors verapamil and cyclosporin A did not inhibit THP efflux. However, genistein, which is a specific inhibitor of multidrug resistance-associated protein (MRP), increased the THP remaining in the resistant cells, and the value was approximately equal to that of the control group in the sensitive cells. These results suggest that THP is taken up into HL60 and HL60/THP cells via a common carrier by facilitated diffusion, and then pumped out in an energy-dependent manner. Furthermore, the accelerated efflux of THP by a specific mechanism, probably involving MRP, other than the expression of P-glycoprotein, resulted in decreased drug accumulation in the resistant cells, and was responsible, at least in part, for the development of resistance in HL60/THP cells.

Analysis of Variance↗
PubMed1996

Inducer expulsion is not a determinant of diauxic growth in Streptococcus bovis.

When Streptococcus bovis JB1 was repeatedly transferred in a medium that contained the non-metabolizable glucose analog, 2-deoxyglucose, it lost its phosphotransferase system (PTS) for glucose but was still able to take up glucose via a facilitated diffusion mechanism. The wild type (JB1) had an inducible enzyme II lactose, but the mutant (JB1(2DG)) had a constitutive lactose PTS. JB1(2DG) was no longer able to exclude lactose when it was provided with glucose, but it retained its ability to expel a non-metabolizable lactose analog. Because JB1(2DG) could utilize glucose and lactose simultaneously and grow in a non-diauxic fashion, it appeared that inducer expulsion was not an important catabolite regulatory mechanism. Based on these results, inducer expulsion may be an artifact of non-metabolizable sugars.

Biological Transport, Active↗
PubMed2002

Branchial and renal excretion of urea and urea analogues in the plainfin midshipman, Porichthys notatus.

This study investigated whether urea transport mechanisms were present in the gills of the ammoniotelic plainfin midshipman (Porichthys notatus), similar to those recently documented in its ureotelic relative (family Batrachoididae), the gulf toadfish (Opsanus beta). Midshipmen were fitted with internal urinary and caudal artery catheters for repetitive sampling of urine and blood in experiments and radiolabeled urea analogues ([(14)C]-thiourea and [(14)C]-acetamide) were used to evaluate the handling of these substances. Isosmotically balanced infusions of urea were used to raise plasma and urine urea concentrations to levels surpassing physiological levels by 8.5-fold and 6.4-fold, respectively. Despite these high urea levels, there was no observable transport maximum in either renal or branchial urea excretion rate, a result mirrored by the total uptake of fish exposed to a range of environmental urea concentrations. Permeability to urea appeared to be symmetrical in the two directions. At comparable plasma concentrations the branchial clearance rate of acetamide was 74% that of urea while branchial clearance rate of thiourea was 55% that of urea. For influx, the comparable values were 60% and 36%, indicating the same pattern. In contrast, the secretion clearance rate of acetamide by the kidney was 56% that of urea while the rate of thiourea secretion clearance was 137% greater than that of urea, with both urea and thiourea being more concentrated in the urine than in the plasma. In addition, the secretion clearance rates of thiourea and urea were significantly greater than those of water and Cl(-), whereas acetamide, water and Cl(-) were found equally in the plasma and urine, appearing to passively equilibrate between the two fluids. Based on our findings, there appear to be two distinct transport mechanisms involved in urea excretion in the plainfin midshipmen, one in the gill (a facilitated diffusion type transporter) and one in the kidney (an active transport mechanism), each of which does not saturate even at plasma urea concentrations that greatly exceed physiological levels. These transporters appear to be similar to those in the midshipman's ureotelic relative, the gulf toadfish.

Animals↗
PubMed2003

CATs and HATs: the SLC7 family of amino acid transporters.

The SLC7 family is divided into two subgroups, the cationic amino acid transporters (the CAT family, SLC7A1-4) and the glycoprotein-associated amino acid transporters (the gpaAT family, SLC7A5-11), also called light chains or catalytic chains of the hetero(di)meric amino acid transporters (HAT). The associated glycoproteins (heavy chains) 4F2hc (CD98) or rBAT (D2, NBAT) form the SLC3 family. Members of the CAT family transport essentially cationic amino acids by facilitated diffusion with differential trans-stimulation by intracellular substrates. In some cells, they may regulate the rate of NO synthesis by controlling the uptake of l-arginine as the substrate for nitric oxide synthase (NOS). The heterodimeric amino acid transporters are, in contrast, quite diverse in terms of substrate selectivity and function (mostly) as obligatory exchangers. Their selectivity ranges from large neutral amino acids (system L) to small neutral amino acids (ala, ser, cys-preferring, system asc), negatively charged amino acid (system x(c)(-)) and cationic amino acids plus neutral amino acids (system y(+)L and b(0,+)-like). Cotransport of Na(+) is observed only for the y(+)L transporters when they carry neutral amino acids. Mutations in b(0,+)-like and y(+)L transporters lead to the hereditary diseases cystinuria and lysinuric protein intolerance (LPI), respectively.

Amino Acid Transport System y+↗
PubMed2003

The SLC22 drug transporter family.

The SLC22 family comprises organic cation transporters (OCTs), zwitterion/cation transporters (OCTNs), and organic anion transporters (OATs). These transporters contain 12 predicted alpha-helical transmembrane domains (TMDs) and one large extracellular loop between TMDs 1 and 2. Transporters of the SLC22 family function in different ways: (1) as uniporters that mediate facilitated diffusion in either direction (OCTs), (2) as anion exchangers (OAT1, OAT3 and URAT1), and (3) as Na(+)/ l-carnitine cotransporter (OCTN2). They participate in the absorption and/or excretion of drugs, xenobiotics, and endogenous compounds in intestine, liver and/or kidney, and perform homeostatic functions in brain and heart. The endogenous substrates include monoamine neurotransmitters, choline, l-carnitine, alpha-ketoglutarate, cAMP, cGMP, prostaglandins, and urate. Defect mutations of transporters of the SLC22 family may cause specific diseases such as "primary systemic carnitine deficiency" or "idiopathic renal hypouricemia" or change drug absorption or excretion.

Animals↗
PubMed2005

Role and regulation of urea transporters.

In the past few years, significant knowledge has been gained about the physiological role and regulation of urea transporters, which have been now cloned in many species. The two major mammalian urea transporters, UT-A and UT-B, have been best studied in the kidney, where they mediate the facilitated diffusion of urea across tubular, interstitial, and vascular compartments, necessary to maintain an osmolar gradient along the renal corticomedullary axis. The genes encoding these transporters, Slc14A2 for UT-A and Slc14A1 for UT-B, have been characterized in rodents and humans, allowing identification of transcriptional mechanisms involved in the regulation of UT-A expression. The crucial role that urea transporters play in renal physiology is underscored by the phenotypic characteristics of UT-A and UT-B knockout mice, in which lack of specific urea transporters impairs the ability to concentrate urine. Expression of the UT-A and UT-B transporters has also been identified in extra-renal sites, where their physiological significance is only beginning to be elucidated. More information on the mechanisms modulating urea transporter expression is becoming available, and the possible involvement of aberrant regulation of these transporters in pathological conditions, or as a result of certain pharmacological treatments, has emerged from recent studies.

Aging↗