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PubMed1998

Organic cation transporters in intestine, kidney, liver, and brain.

This review focuses on sodium-independent transport systems for organic cations in small intestine, liver, kidney, and brain. The roles of P-glycoproteins (MDR) and anion transporters (OATP) in organic cation transport are reported, and two members of the new transporter family OCT are described. The OCT transporters belong to a superfamily that includes multidrug-resistance proteins, facilitative diffusion systems, and proton antiporters. They mediate electrogenic transport of small organic cations with different molecular structures, independently of sodium and proton gradients. The current knowledge of the distribution and functional properties of cloned cation transport systems and of cation transport measured in intact plasma membranes is used to postulate identical or homologous transporters in intestine, liver, kidney, and brain.

Amino Acid Sequence↗
PubMed1978

Effects of phloretin and theophylline on 3-O-methylglucose transport by intestinal epithelial cells.

Phloretin and theophylline each exert an immediate inhibitory effect on the Na+-independent, facilitated-diffusion transport system for sugar associated with intestinal epithelial cells. Phloretin inhibits approximately 50% more of the total Na+-independent sugar flux than theophylline. Neither agent has an immediate effect on the Na+-dependent, concentrative sugar transport system, although preincubation of the cells with phloretin causes a significant inhibition. The slowly developing effect is correlated with a decrease in cellular adenosine triphosphate (ATP) and an elevation of intracellular Na+. Other agents which elevate cell Na+ also inhibit Na+-dependent sugar influx, even if ATP levels are not depleted. On the other hand, if ATP is depleted by phloretin under conditions in which the cells do not gain Na+, the inhibitory effect on Na+-dependent sugar flux tends to disappear. The slow-onset phloretin effects are due to transinhibition of the Na+-dependent sugar carrier by cellular Na+. When the passive sugar carrier is inhibited by phloretin or theophylline, the concentrative system can establish an enhanced sugar gradient. Because of the secondary metabolic effects of phloretin, theophylline induces a greater gradient enhancement despite its more limited effect on the passive sugar-transport system. Sugar gradients as large as 20-fold are induced by theophylline, in contrast to 12-fold gradients observed in the presence of phloretin and approximately 7- to 8-fold for untreated cells. These results are discussed in terms of conceptual questions regarding the energetics of Na+-dependent transport systems.

Adenosine Triphosphate↗
PubMed1979

Energetics of sugar transport by isolated intestinal epithelial cells: effects of cytochalasin B.

The capability of isolated intestinal epithelial cells to establish concentration gradients of 3-O-methylglucose (3-OMG) by a Na+-dependent transport system is limited by concomitant function of a Na+-independent, facilitated diffusion transport system. Monosaccharides accumulated by the active system are continuously lost via the passive system, which acts to lower steady-state sugar gradients maintained by the cell. Cytochalasin B is a potent inhibitor of the passive system and allows the cells to establish a sugar gradient that is much higher than normal. When extracellular [3-OMG] is 1 mM, cytochalasin induces sugar accumulation ratios of 30-fold (+/- phlorizin) in contrast to control ratios of approximately 10-fold. When [3-OMG] is 0.1 mM, cytochalasin (0.1 mM) induces 40-fold accumulation ratios. When changes in extracellular sugar concentration are considered, steady-state concentration gradients observed are 70-fold. For a Na:sugar coupling stoichiometry of 1:1, gradients of this magnitude represent the approximate theoretical maximum for a transport system driven exclusively by the transmembrane electrochemical potential for Na+.

Animals↗
PubMed1980

Monosaccharide transport across microvillous membrane of human placenta.

Transport through the microvillous membrane of the syncytium is the first step in placental transfer of nutrients. We have therefore studied glucose transport by isolated microvillous membrane vesicles. Transport occurred by selective and rapid facilitated diffusion, which was inhibited by phloridzin, phloretin, cytochalasin B, and HgCl2. Nonmediated diffusion of the substrate was found by three independent methods to be very slow. Competition studies showed that aldohexoses in the C-1 chair conformation were the preferred substrates. Transport was independent of sodium gradients and was not modulated by insulin. However, several steroids inhibited transport including estriol and progesterone, which are abundant in utero. Kinetic analysis by equilibrium exchange demonstrated a Km of 31 mM and a Vmax of 120 nmol . s-1 . mg protein-1. The Km and Vmax suggest a large capacity in relation to calculated fetal needs. In consequence of this capacity, intrasyncytial concentrations of glucose are probably maintained near those of maternal blood. Augmentation of transport at this membrane by hormones or other agents is unlikely to increase fetal supply of glucose, but down regulation by steroids may serve a regulatory function.

Biological Transport↗
PubMed1983

Influence of organic acids on intracellular pH.

By use of double-barreled pH-sensitive microelectrodes, intracellular pH was measured in isolated sheep cardiac Purkinje strands. After equimolar substitution of 20 mmol/l Cl- by several organic anions at constant extracellular pH 6.8, the rate of induced intracellular acidification was measured. For many organic acids tested, a relation was found between the rate of intracellular acidification and the product of their dissociation constant (pK'a) and diisopropylether-to-water partition ratio (p'). L-Lactate and pyruvate, and also cyanoacetate and alpha-ketobutyrate, caused faster acidifications than anticipated from their pK'a and p'. The rate of intracellular acidification, induced by L-lactate and pyruvate, was markedly depressed in the presence of 4 mmol/l alpha-cyano-4-hydroxycinnamate, a known inhibitor of the carrier-mediated pyruvate transport. The drug also had an effect on the acidification produced by cyanoacetate, alpha-ketobutyrate, glycolate, alpha-hydroxybutyrate, and alpha-chloropropionate, but not on that produced by propionate and acetate. L-Lactate caused a faster acidification than D-lactate. Our results suggest the existence of a facilitated diffusion for L-lactate, pyruvate, and some other organic acids in sheep Purkinje cells.

Animals↗
PubMed1984

Transport of water and urea in red blood cells.

Evidence for water channels in red blood cells is reviewed. In an entropically driven reaction, organic mercurials decrease water permeability, elevate the activation energy, and reduce the ratio of osmotic to diffusional water permeabilities to unity so that water transport properties of red blood cells are hardly distinguishable from lipid bilayers. It is concluded that mercurials close the water channels. A variety of kinetic, pharmacological, and comparative evidence converges on the conclusion that urea and other solutes are excluded from water channels. Urea apparently permeates the red cell membrane via a facilitated diffusion system, which plays an important role when red blood cells traverse the renal medulla; rapid urea transport helps preserve the osmotic stability and deformability of the cell, and it helps prevent dissipation of extracellular osmotic gradients. Water apparently traverses the channel via a single-file mechanism; the very low channel permeability of H+ is explained if the channel contains fixed charge, or alternatively, if the mobile water molecules within the channel do not form a continuum. An alternative unitary pore hypothesis for simultaneous transport of water, ions, and small solutes is also discussed.

Biological Transport↗
PubMed1987

Dependence of L-arginine accumulation on membrane potential in cultured human fibroblasts.

The cell-to-medium distribution ratios at steady state of L-arginine (RArg) and of the lipid-soluble cation tetraphenylphosphonium (RTPP) were studied as a function of the membrane potential (Em) in adult human fibroblasts. The relationship between RArg and Em was qualitatively similar to that of RTPP and Em. Quantitatively, RArg and RTPP differed in that 1) RTPP was much greater than RArg when Em was near zero, indicating a significant binding component in the uptake of TPP+ but not of L-arginine, and 2) after a correction for binding when Em is near zero, RTPP was still greater than RArg so that RT/F . ln RTPP exceeded RT/F . ln RArg by 10-25 mV. The pattern of the redistribution of accumulated TPP+ and arginine after an alteration of Em was identical. In null-point experiments, the external [K+] for which there were no changes in cellular TPP+ or L-arginine in the presence of high valinomycin (the null points) were very similar for the two probes. Em calculated from the null-point measurements (-70(-)-80 mV) was also very similar to RT/F . ln RArg and thus smaller than RT/F.ln RTPP. It was concluded that 1) there was an additional TPP+ binding as cellular [TPP] rose in response to more negative membrane potentials, 2) the transport system for L-arginine in these cells (system y+) operates as a facilitated diffusion system driven by the membrane potential, and 3) in some circumstances, L-arginine could be employed as a probe of Em.

Arginine↗
PubMed1988

Osmotic stability of red cells in renal circulation requires rapid urea transport.

Urea transport by the human erythrocyte occurs via an asymmetric-facilitated diffusion system with high Michaelis constants and high maximal velocities; the equivalent permeability in the limit of zero urea concentration is approximately 10(-3) cm/s (J. Gen. Physiol. 81: 221-237, 239-253, 1983). A physiological role for this system is revealed by numerical integration of the appropriate equations that show that rapid urea transport is essential for red cell stability in passing through the renal medulla. The calculation compares two cells. Cell A transports urea with permeability characteristics of normal red cells; cell B has urea permeability similar to lipid bilayers. On entering the hypertonic medulla, both cells shrink, but only B swells on leaving the medulla. The osmotic stress for cell B is greater than for A. Cell B is close to hypertonic hemolysis in the medulla and to hypotonic hemolysis in the cortex. Cell B remains swollen for some time after its exit; the resulting decreased deformability presents a hazard if B reenters the microcirculation. Furthermore, cell B removes a significant fraction of the filtered load of urea and compromises the osmotic gradients in the medulla.

Algorithms↗
PubMed1990

Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells.

The "liver" isoform of the facilitated diffusion glucose transporter is expressed predominantly in liver, intestine, kidney, and pancreatic islet beta-cells. The apparent molecular mass of the transporter in liver, kidney, and intestine is different, as detected by Western blot analysis of membrane proteins using antipeptide antibodies. However, as assessed by Northern blot analysis and molecular cloning, the same mRNA is expressed in these tissues, indicating that there are tissue-specific posttranslational modifications of the same transporter polypeptide. As determined by immunofluorescence analysis on frozen tissue sections, the liver glucose transporter is present on the sinusoidal membrane of hepatocytes, on the basolateral membrane of fully differentiated absorptive intestine epithelial cells, and on the basolateral membrane of proximal tubule cells of the kidney nephron. This localization is consistent with the involvement of the liver glucose transporter in several key steps of glucose metabolism: glucose uptake and release by the liver and absorption or reabsorption by epithelial cells of the intestine and kidney, respectively.

Animals↗
PubMed1994

Adenosine transport in cultured human umbilical vein endothelial cells is reduced in diabetes.

Adenosine transport in cultured human umbilical vein endothelial cells (HUVEC) was characterized and shown to be mediated by a single facilitated diffusion mechanism. Initial rates of adenosine influx at 22 degrees C were saturable [apparent Michaelis constant, 69 +/- 10 microM; maximum velocity (Vmax), 600 +/- 70 pmol.10(6) cells-1.s-1] and inhibited by nitrobenzylthioinosine (NBMPR). Formycin B had an unusually high affinity [inhibitory constant (Ki), 18 +/- 4.3 microM], whereas inosine had a low affinity (Ki, 440 +/- 68 microM) and nucleobases were without effect on adenosine influx. The number of transporters (1.2 x 10(6) sites/cell) was estimated by NBMPR equilibrium binding (apparent dissociation constant, 0.11 +/- 0.01 nM; maximum binding, 2.0 +/- 0.15 pmol/10(6) cells). In addition, we compared these endothelial cells with those obtained from cords from pregnancies complicated by diabetes (HUVEC-D), since embriopathy may occur in these conditions. HUVEC-D exhibited a 2.3-fold reduction in both the Vmax for adenosine influx and the maximum number of NBMPR binding sites (260 +/- 40 pmol.10(6) cells-1.s-1 and 0.86 +/- 0.08 pmol/10(6) cells, respectively). However, the turnover number for each nucleoside transporter in normal and diabetic HUVEC was similar (approximately 300 adenosine molecules/s). Adenosine metabolism at 10 microM in HUVEC-D was modified compared with normal cells. Intracellular phosphorylation (> 90%) was the predominant pathway in normal HUVEC, whereas in HUVEC-D, substantial levels of adenine and adenosine were detected. The present results demonstrate therefore the downregulation of the NBMPR-sensitive nucleoside transporter and changes in adenosine metabolism in HUVEC from diabetic pregnancies.

Adenosine↗
PubMed1996

Bovine adrenal endothelial cells express nucleoside transporters nonregulated by protein kinases A and C.

The present investigation characterizes the nucleoside transporters in bovine adrenomedullary endothelial cells and their possible regulation by the action of protein kinases A and C to establish comparisons with the nucleoside transport system in chromaffin cells. The nucleoside transport proved to be a nitrobenzylthioinosine (NBTI)-sensitive facilitated-diffusion system with high affinity for adenosine. These endothelial cells had a high density of nucleoside transporters (660,000 +/- 130,000 transporters/ cell), measured by NBTI binding, and the efficiency was close to 2 adenosine molecules internalized transporter-1.s-1. The stimulation of the cells with bradykinin and P1,P4-di(adenosine-5')tetraphosphate, which raise the intracellular Ca2+ concentration, did not modulate the adenosine transport. When the cells were stimulated with signals coupled to adenosine 3',5'-cyclic monophosphate intracellular production, such as norepinephrine and isoproterenol, the adenosine transport was not modified. Furthermore, the treatment of the cells with direct activators of both protein kinases A and C had no effect on adenosine transport, in contrast to that reported in chromaffin cells.

Adenosine↗
PubMed2002

Vitamin D-inducible calcium transport and gene expression in three Caco-2 cell lines.

The parental cell line (P) of Caco-2 cells and two clones, BBe and TC7, were studied at 11 days postconfluence to test the facilitated diffusion model of vitamin D-mediated intestinal calcium absorption (CaTx). Nuclear vitamin D receptor (nVDR) and calbindin D(9k) (CaBP) were measured by Western blot; 1,25-hydroxyvitamin D(3) 24-hydroxylase (CYP24), CaBP, plasma membrane Ca-ATPase (PMCA), and Ca transport channel (CaT1) mRNA levels were examined by RT-PCR; and net apical-to-basolateral CaTx was examined after treating cells with vehicle or 10 nM calcitriol for 8 (mRNA levels) or 48 h (protein, CaBP mRNA, CaTx). nVDR level was lowest in BBe (38% P value) and directly related to CYP24 induction (TC7 = P, which were 1.56 times greater than BBe). nVDR was inversely related to the vitamin D-induced levels of CaT1 mRNA, CaBP mRNA, PMCA mRNA, and net CaTx, with the highest induction seen in BBe. Basal CaBP mRNA (86 times greater than P) and protein levels were highest in TC7 cells and were not associated with higher net CaTx, suggesting CaBP may not be rate limiting for CaTx in these cells.

Absorption↗
PubMed1989

Basolateral inositol transport by intestines of carnivorous and herbivorous teleosts.

Myoinositol transport by isolated basolateral membrane vesicles was characterized from intestines of the herbivorous tilapia (Oreochromis mossambicus) and the carnivorous eel (Anguilla anguilla). [3H]myoinositol transport occurred by nonelectrogenic, facilitated diffusion independent of cation gradients and was inhibited by phloretin (Ki = 0.6 and 0.9 mM for tilapia and eel, respectively) but not by phloridzin. Kinetic analysis of myoinositol influx disclosed no differences in concentration yielding half-maximal influx or maximum influx between these species. D-Glucose inhibition of myoinositol influx was shown to be noncompetitive. Additional inhibition studies with a range of sugars demonstrated that aldohexoses in the C-1 chair conformation were preferred substrates. Myoinositol had no inhibitory effect on D-glucose transport. Preloading vesicles with myoinositol transstimulated [3H]myoinositol uptake, while the use of internal D-glucose was without effect. These basolateral data support the contention that epithelial myoinositol carriers are separate from D-hexose transport systems present on the same membrane but are modulated by hexose binding to a regulator site on the myoinositol transporter. Furthermore, the comparison of two fish species suggests that genetic dietary transport adaptation occurs on the brush-border membrane, while no such adaptation is present at the epithelial basolateral pole.

Anguilla↗
PubMed1991

Mechanism of arachidonic acid transport across rabbit distal colonic mucosa.

The initial rate of [1-14C]arachidonic acid (AA) entry in the serosal side of rabbit distal colonic mucosa mounted in Ussing-type chambers is linear and independent of intracellular metabolism. When the maximal AA uptake was plotted as a function of medium AA concentration in ranges between 50 and 500 nM, saturation of the AA uptake with increasing concentrations was observed. The time course of the uptake of oleic acid and palmitic acid was similar to that observed with AA, and their separate addition to incubation medium strongly reduced the AA uptake. The influx of arachidonate was largely inhibited by ouabain and by incubation with mucosal sodium-free solution and amiloride, while it was increased when colonic mucosa was exposed to luminal amphotericin B. However, voltage-clamp studies showed that the AA entry rate appeared to be linearly related (r = 0.99) to transepithelial potential difference (PD) and suggested that the sodium dependence of AA translocation is an indirect effect of the changes in transepithelial PD induced by sodium transport shifts. These features provide evidence that there is a common entry pathway for AA and other long-chain free fatty acids mediated by a mechanism of facilitated diffusion driven by transmembrane PD.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1994

Carrier-mediated electrogenic transport of estradiol-17 beta-glucuronide in rat liver BMV.

Estradiol-17 beta-glucuronide (E(2)17G) is one of a series of naturally occurring glucuronide conjugates of the steroid D-ring that induce cholestasis in the rat and nonhuman primate. The present studies characterized the transport of [3H]E(2)17G in basolateral membrane vesicles (BMVs) from male rat liver. The uptake of E(2)17G was temperature dependent, occurred into an osmotically sensitive space, and was saturable, with an apparent Michaelis constant and maximal velocity of 13 microM and 29 pmol.mg protein-1.5 s-1, respectively. Uptake was not coupled to the uptake of Na+ nor to Cl-or OH- exchange but was markedly stimulated by an inside-positive membrane potential. Bromosulfophthalein inhibited the uptake of E217G noncompetitively; estriol-16 alpha-glucuronide, but not estradiol-3-glucuronide or estradiol-3-SO4-17 beta-glucuronide, inhibited the uptake of E(2)17G. Thus E(2)17G is transported as an anion by facilitated diffusion by a system that differs from the multispecific Na(+)-taurocholate cotransport system and the bromosulfophthalein transport system.

Animals↗
PubMed1978

Myoglobin function in the isolated fluorocarbon-perfused dog heart.

An isolated dog heart preparation perfused with hemoglobin-free fluorocarbon suspension has been developed to study the role of myoglobin in myocardial function. The coronary vasculature was perfused at constant flow, with oxygen consumption determined from arteriovenous PO2 differences. Muscle function was assessed by measurement of pressures generated in a latex balloon placed in the left ventricle. The perfusate consisted of 20% perfluorotributylamine and 80% Ringer's lactate with 16 mM glucose. Steady-state oxygen consumption decreased from 0.30 to 0.11 ml/min per gram dry weight left ventricle, as perfusate PO2 decreased from 690 to 150 mmHg. Left ventricular pressure generation and oxygen consumption were determined before and after addition of 8 mM sodium nitrite, which changed functional ferrous myoglobin to high-spin ferric myoglobin. Over the range of perfusate PO2 studied, nitrite addition did not alter mechanical performance or myocardial oxygen consumption. These data suggest that those conditions necessary for substantial myoglobin-facilitated diffusion of oxygen in the myocardium are not present in the isolated fluorocarbon-perfused dog heart.

Animals↗
PubMed1986

O2 gradients from sarcolemma to cell interior in red muscle at maximal VO2.

The intracellular distribution of O2 in cross sections of dog gracilis muscles was determined by myoglobin (Mb) cryospectrophotometry. The volume sampled by the photometer was approximately 30 micron3 and contained 1-2 mitochondria. Measurements could be made to within 3 micron of capillaries without interference from hemoglobin. Mb saturation was uniform at all loci examined when respiration was blocked with cyanide. During twitch contraction at maximum O2 consumption, saturations within a cell cross section varied by up to 20%. The corresponding difference in partial pressure of O2 (PO2) was 1.5 Torr. Circumferential O2 gradients parallel to and 5 micron from the sarcolemma were greatest near capillaries. They did not exceed 0.1 Torr/micron and were dissipated within 25 micron of the sarcolemma. Gradients perpendicular to the sarcolemma were less than 0.02 Torr/micron. Saturation was not significantly correlated with cell diameter. Minimum PO2 was seldom located at the center of the cell cross section. Differences in saturation between contiguous cells often exceeded 10%. The distribution of O2 within cells appeared to reflect both an intercellular O2 flux and and an O2 flux from adjacent capillaries. Data agree qualitatively and quantitatively with mathematical models that take account of the particulate nature of blood and facilitated diffusion by Mb.

Animals↗
PubMed1998

Direct observation of radial intracellular PO2 gradients in a single cardiomyocyte of the rat.

The purpose of the present study was to directly visualize radial gradients of intracellular PO2 in a single individual cardiomyocyte isolated from the rat ventricle. Microspectrophotometry with the use of cytosolic myoglobin as an oxygen probe was conducted at 410 nm. When the quiescent cell was incubated with 1 microM carbonyl cyanide m-chlorophenylhydrazone to increase oxygen consumption approximately eightfold, gradual decreases in myoglobin oxygen saturation (SMb) were demonstrated toward the core of the cell, whereas these decreases disappeared when the cell was treated with 2 mM NaCN. These results highlighted the importance of diffusional oxygen transport in determining intracellular oxygenation in cardiac cells. From the measured SMb, we assessed the profile of radial changes in intracellular PO2 at the mean SMb comparable to that in vivo ( approximately 0.5). Quite steep PO2 gradients were demonstrated in the vicinity of the sarcolemma that were rapidly attenuated toward the cell core. These radial profiles of intracellular PO2 demonstrate the significance of myoglobin-facilitated diffusion of oxygen. Furthermore, the shallow gradients of PO2 near the center of the cell might arise from partial depression of oxygen consumption near the cell core.

Animals↗